Compositions and methods comprising substituted 2-aminoimidazoles

ABSTRACT

The present invention presents 2-(acylamino)imidazoles with therapeutic activity, including selective activity against cancer cells, and compositions comprising them. Methods of using and preparing the 2-(acylamino)imidazoles are also presented.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a continuation of International PatentApplication No. PCT/US2018/025730, filed Apr. 2, 2018, which claims thepriority of U.S. Provisional Patent Application No. 62/480,173 (filedMar. 31, 2017), the disclosures of which are herein incorporated byreference in their entirety for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

Part of the work leading to this invention was carried out with U.S.Government support provided by the National Institute of Health (NIHGrant Nos. 2R01-RGM090082-A1 and R01 CA140296). The U.S. Governmenttherefore has certain rights in this invention.

FIELD OF THE INVENTION

In some embodiments, the present invention is directed to compositionsand methods comprising 2-(acylamino)imidazoles, including theirregioselective preparation and medical uses.

BACKGROUND OF THE INVENTION

Tuberculosis is a world-wide health threat. Agents that can effectivelykill this bacterium while maintaining moderate cytotoxicity hold promiseto treat this disease in humans. Given the advent of both multi-drugresistant (MDR) and completely drug resistant (XDR) strains of thispathogen, development of a “next-generation” series of small moleculesto treat this disease could provide great benefits.

Naamidine A, a natural product isolated from the marine sponge Leucettachagosensis, displays anti-proliferative activity against bothMycobacterium tuberculosis (IC₅₀=0.94 μM or 0.41 μg/mL) and Candidaalbicans (MIC₁₀₀=0.78 μM). The related natural products kealiinines Band C also display anti-tubercular activity (IC₅₀=8.9 μM and 42 μMrespectively). Naamidine A has been shown to be relatively welltolerated in vivo for mouse models, with a maximum tolerated dose of 25mg/Kg (see Ireland et al., J. Med. Chem. 1998, 41, 3909). Further, inCEM-TART cells, the IC₅₀=34.8 μM, which indicates a selectivity ratio of37.

Naamidine A also displays selective anti-cancer activity of therapeuticinterest. See, e.g., U.S. Pat. No. 5,574,057. Many cancer drugs arenearly indiscriminate in their cytotoxicity and affect healthy and tumorcells comparably. The resulting narrow therapeutic treatment windowslimit both the amount of drug that can be administered to patients andthe duration of treatment, reducing the overall efficacy of the therapy.Additionally, the adverse side effects arising from low therapeuticindices can necessitate additional palliative care efforts and furtherburden patient recovery. In contrast, naamidine A selectively inhibitsproliferation of cancerous cells, thereby providing a potentialadvantage over less selective agents.

Naamidine A's activity may partially arise from its ability tocoordinate zinc. Zinc is an essential trace metal; it is estimated that10% of the proteome may bind zinc, with 40% of these proteinsfunctioning as transcription factors and the remaining 60% operating inan enzymatic or an ion transport capacity. Andreini et al. J ProteomeRes 2005; 5(1):196-201. Perturbations in zinc homeostasis are correlatedwith various disease states, and in the case of breast cancer, increasedzinc levels have been observed in malignant breast tissue compared tononmalignant tissue. Margalioth et al. Cancer 1983; 52(5):868-72; Gerakiet al. Phys Med Biol 2004; 49(1):99. As such, exploiting differences inzinc homeostasis between healthy and diseased tissue may provide newavenues for the development of anti-cancer therapeutics.

Despite naamidine A's promise as a therapeutic agent, its1H-imidazole-2,5-dione substituent complicates its preparation andevaluation as a possible drug. Simpler, easier-to-make analogs ofnaamidine A possessing therapeutically interesting activity, especiallyanti-tubercular or anti-cancer activity, would present advantages overnaamidine A itself, especially if the analogs were available by anefficient synthetic route.

The present invention's 2-aminoimidazole compositions and methodspresent embodiments with these and other advantages.

BRIEF SUMMARY OF THE INVENTION

In a first embodiment, the invention presents a 2-(acylamino)imidazolecompound of structure I:

or a salt thereof;wherein:

R¹ is a member selected from the group including alkyl, alkenyl,alkynyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;

X is a member selected from the group including a bond, O, and NR^(5a);

Y is a member selected from the group including O, S, or NR^(5b); or,when X is O or a bond, Y is O;

R² is a member independently selected from the group including alkyl,alkenyl, alkynyl, and arylalkyl; or, alternatively, R² and R⁷ join toform an additional heterocyclyl fused ring;

R⁴ is a member independently selected from the group including aryl andheteroaryl, wherein R⁴ is unsubstituted or has from one to five R^(6a)substituents;

R^(5a) and R^(5b) are each a member independently selected from thegroup including hydrogen, alkyl, fluoroalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, arylalkyl, and heteroarylalkyl;

each of the R^(6n) members is independently selected from the groupincluding alkyl, hydroxy, alkoxy, aminoalkoxy, alkylamino,alkylaminoalkoxy, alkenyl, alkynyl, aryl, aryloxy, arylamino,cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkoxy,cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocycyloxy,heterocycylalkyloxy, heterocycylamino, heterocycylalkylamino, halo,haloalkyl, fluoroalkyloxy, arylalkyl, arylalkyloxy, arylalkylamino,heteroaryl, heteroaryloxy, heteroarylamino, heteroarylalkyl,heteroarylalkyloxy, and heteroarylalkylamino; or, alternatively, a pairof adjacent R^(6n) members join to form an additional fused ring that isselected from the group including cycloalkyl, aryl, heterocyclyl, andheterocycloaryl; and

R⁷ is a member independently selected from the group including hydrogen,halo, trifluoromethyl, and alkyl; or, alternatively, R² and R⁷ join toform an additional heterocyclyl fused ring. In some preferred aspects ofthe first embodiment, the 2-(acylamido)imidazole compound is not anatural product.

In some embodiments, the invention presents a composition fortherapeutic use, the composition including a 2-(acylamino)imidazole ofone of the aspects herein. In some aspects, the composition furtherincludes a pharmaceutically acceptable excipient.

In a second embodiment, the invention presents a method of killingbacteria in vitro, the method including treating the bacteria with acomposition set forth in the first embodiment or one of its aspects.

In a third embodiment, the invention presents a method of killingbacteria in vivo, the method including administering a composition setforth in the first embodiment or one of its aspects to a patient.

In a fourth embodiment, the invention presents a method of treatingcancer, the method including administering a composition set forth inthe first embodiment or one of its aspects to a patient with cancer,thereby treating the patient.

In a fifth embodiment, the invention presents a method of selectivelypreparing a 4-substituted imidazole, the method including the steps:

-   -   cyclizing an α-alkylamino ketone and an acyl cyanamide to form a        2-N-acyl imidazolidin-2-imine product; and    -   converting the 2-N-acyl imidazolidin-2-imine to a        2-acylaminoimidazole product; wherein the 2-acylamino product is        substantially free from 1-acyl and 3-acyl regioisomers (e.g.,        <2% or <1% of such products). In some aspects, the cycling step        comprises an acid catalyst. In some preferred aspects, the        2-acylamino product is substantially free from N²,N²-diacyl        products (e.g., <2% or <1% of such products).

In a sixth embodiment, the invention presents a method of selectivelypreparing a 2-acylamino 4-substituted imidazole, the method comprisingthe steps:

-   -   monoalkylating an α-amino acid, ester, or amide at the α-amino        group;    -   converting the α-alkylamino acid, ester, or amide to an        α-alkylamino ketone;    -   cyclizing the α-alkylamino ketone and an acyl cyanamide to form        a 2-N-acyl imidazolidin-2-imine product; and    -   converting the 2-N-acyl imidazolidin-2-imine to a        2-acylaminoimidazole product; wherein the 2-acylamino product is        substantially free from 1-acyl and 3-acyl regioisomers (e.g.,        <2% or <1% of such products). In some aspects, the cycling step        comprises an acid catalyst. In some preferred aspects, the        2-acylamino product is substantially free from N²,N²-diacyl        products (e.g., <2% or <1% of such products).

In a seventh embodiment, the invention presents a method of inducingmetal ion dyshomeostasis, the method including the steps of:

-   -   causing the composition of the first embodiment or one of its        aspects to contact a metal ion, thereby forming a chelated        complex, wherein the chelated complex forms outside a lysosome;    -   allowing the chelated complex to enter the lysosome;    -   allowing the chelated complex to dissociate within the lysosome,        thereby increasing the internal concentration of the metal ion.        In some aspects, the metal ion is Zn²⁺. In some aspects, the        dyshomeostasis causes cell death.

Additional embodiments of the present invention are apparent from theDetailed Description, Examples, and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the structure of naamidine A, its biological source, and asuccessful approach to its synthesis.

FIG. 2 shows a route to synthesis of naamidine A analogs.

FIG. 3 shows the structure and anticancer activity of ZNA. ZNA'sperformance is rated on growth inhibition of chemoresistant breastcancer patient pleural effusion cells (PE1007070) versus non-transformedmammary tissue (hTERT-HMEC).

FIG. 4 shows a comparison of the effects of ZNA and naamidine A on cellviability.

FIG. 5 shows a route to synthesis of naamidine A analogs.

FIG. 6 shows the zinc affinity of ZNA.

FIG. 7 shows the results of an in vivo study of the effects of ZNA oninduced tumors in mice. EF1α-PyMT tumors were induced in mice andincubated for 21 days. They were treated with ZNA (100 mg/kg), ZnSO₄,and ZNA+ZnSO₄.

FIG. 8 shows the results of a mammary branching assay.

FIG. 9 shows a synthetic route toward 2-N-acyl-4-arylimidazoles (i.e.,C⁴-aryl-N²-acylaminoimidazoles).

FIG. 10 shows the structures of some analogs.

FIG. 11 shows a comparison of the solubility of several ZNA analogs withand without zinc.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. In addition, the materials, methods, andexamples are illustrative only and not intended to be limiting. Allpublications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety,including the U.S. Provisional Application designated by docket number96175-890651-000800US (i.e., U.S. Provisional Appl. No. 62/051,837) andU.S. Pat. Appl. Publ. No. 2013/0197049. In case of conflict, the presentspecification, including these definitions, will control.

The terms “a,” “an,” or “the” as used herein not only includes aspectswith one member, but also includes aspects with more than one member.For example, an embodiment including “a 2-(acylamino)imidazole and anexcipient” should be understood to present certain aspects with at leasta second 2-(acylamino)imidazole, at least a second excipient, or both.

The term “about” as used herein to modify a numerical value indicates adefined range around that value. If “X” were the value, “about X” wouldgenerally indicate a value from 0.90X to 1.10X. Any reference to “aboutX” specifically indicates at least the values X, 0.90X, 0.91X, 0.92X,0.93X, 0.94X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X,1.04X, 1.05X, 1.06X, 1.07X, 1.08X, 1.09X, and 1.10X. Thus, “about X” isintended to teach and provide written description support for a claimlimitation of, e.g., “0.98X.” When the quantity “X” only includeswhole-integer values (e.g., “X carbons”), “about X” indicates from (X−1)to (X+1). In this case, “about X” as used herein specifically indicatesat least the values X, X−1, and X+1.

When the term “about” is applied to the beginning of a numerical range,it applies to both ends of the range. Thus, “from about 5 to 20%” isequivalent to “from about 5% to about 20%.” When “about” is applied tothe first value of a set of values, it applies to all values in thatset. Thus, “about 7, 9, or 11%” is equivalent to “about 7%, about 9%, orabout 11%.” However, when the modifier “about” is applied to describeonly the end of a range or only a later value in a set of values, itapplies only to that value or that end of the range. Thus, the range“about 2 to 10” is the same as “about 2 to about 10,” but the range “2to about 10” is not.

The term “acyl” as used herein includes an alkanoyl, aroyl,heterocycloyl, or heteroaroyl group as defined herein. Examples of acylgroups include, but are not limited to, acetyl, benzoyl, and nicotinoyl.

The term “agent” as used herein includes a compound or mixture ofcompounds that, when added to a composition, tend to produce aparticular effect on the composition's properties. For example, acomposition comprising a thickening agent is likely to be more viscousthan an otherwise identical comparative composition that lacks thethickening agent.

The term “alkanoyl” as used herein includes an alkyl-C(O)— group whereinthe alkyl group is as defined herein. Examples of alkanoyl groupsinclude, but are not limited to, acetyl and propanoyl.

The term “alkenyl” as used herein includes a straight or branched chainhydrocarbon containing at least one carbon-carbon double bond. The chainmay contain an indicated number of carbon atoms. For example, “C₁-C₁₂alkenyl” indicates that the group may have from 1 to 12 (inclusive)carbon atoms and at least one carbon-carbon double bond. When theindicated number of carbon atoms is 1, then the C₁ alkenyl is doublebonded to a carbon (i.e., a carbon analog to an oxo group). In certainaspects, the chain includes 1 to 12, about 2 to 15, about 2 to 12, about2 to 8, or about 2 to 6 carbon atoms. Examples of an alkenyl group mayinclude, but are not limited to, ethenyl (i.e., vinyl), allyl, propenyl,butenyl, crotyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl,dodecenyl, cyclopentenyl, cyclohexenyl, 2-isopentenyl, allenyl,butadienyl, pentadienyl, 3-(1,4-pentadienyl), and hexadienyl.

In some preferred aspects, an alkenyl group is unsubstituted. In someaspects, an alkenyl group is optionally substituted. When optionallysubstituted, one or more hydrogen atoms of the alkenyl group (e.g., from1 to 4, from 1 to 2, or 1) may be replaced with a moiety independentlyselected from the group including fluoro, hydroxy, alkoxy, amino,alkylamino, acylamino, thio, and alkylthio, with the proviso that nohydrogen atom substituent on the carbon-carbon double bond is replacedby a hydroxy, amino, or thio group.

As used herein, the term “alkoxy” refers to a straight or branched chainsaturated or unsaturated hydrocarbon containing at least one oxygen atomin an ether group (e.g., EtO—). The chain may contain an indicatednumber of carbon atoms. For example, “C₁-C₁₂ alkoxy” indicates that thegroup may have from 1 to 12 (inclusive) carbon atoms and at least oneoxygen atom. Examples of C₁-C₁₂ alkoxy groups include, but are notlimited to, methoxy, ethoxy, isopropoxy, butoxy, n-pentoxy, isopentoxy,neopentoxy, and hexoxy.

An alkoxy group can be unsubstituted or optionally substituted. Whenoptionally substituted, one or more hydrogen atoms of the alkoxy group(e.g., from 1 to 4, from 1 to 2, or 1) may be replaced with one or moremoieties independently selected from the group including fluoro,hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio, withthe proviso that any hydrogen atom alpha to the ether oxygen, ifreplaced, may only be replaced by fluoro or alkoxy.

The term “alkyl” as used herein includes an aliphatic hydrocarbon chainthat may be straight chain or branched. The chain may contain anindicated number of carbon atoms: For example, C₁-C₁₂ indicates that thegroup may have from 1 to 12 (inclusive) carbon atoms in it. If nototherwise indicated, an alkyl group about 1 to about 20 carbon atoms. Insome aspects, alkyl groups have 1 to about 12 carbon atoms in the chain.In some aspects, alkyl groups (“lower alkyl”) have 1 to about 6 carbonatoms in the chain. In some aspects, alkyl groups have 1 to about 4, 3,or 2 carbon atoms in the chain. Examples may include, but are notlimited to, methyl, ethyl, propyl, isopropyl (iPr), 1-butyl, 2-butyl,isobutyl (iBu), tert-butyl, pentyl, 2-methylbutyl, 1,1-dimethylpropyl,hexyl, heptyl, octyl, nonyl, decyl, docecyl, cyclopentyl, or cyclohexyl.In some aspects, an alkyl group can exclude methyl (e.g., 2 to 6 carbonatoms in the chain). In some aspects, an alkyl group can be methyl.

An alkyl group can be unsubstituted or optionally substituted. Whenoptionally substituted, one or more hydrogen atoms of the alkyl group(e.g., from 1 to 4, from 1 to 2, or 1) may be replaced with a moietyindependently selected from the group including fluoro, hydroxy, alkoxy,amino, alkylamino, acylamino, thio, and alkylthio.

The term “alkynyl” as used herein includes a straight, branched, orcyclic hydrocarbon containing at least one carbon-carbon triple bond.Examples may include, but are not limited to, ethynyl, propargyl,propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl,decynyl, or decynyl.

An alkynyl group can be unsubstituted or optionally substituted. Whenoptionally substituted, one or more hydrogen atoms of the alkynyl group(e.g., from 1 to 4, from 1 to 2, or 1) may be replaced with a moietyindependently selected from the group including fluoro, hydroxy, alkoxy,amino, alkylamino, acylamino, thio, and alkylthio, with the proviso thatno sp hydrogen atom substituent is replaced by a hydroxy, amino, or thiogroup.

As used herein, the term “2-aminoimidazole” refers to a compound havingthe general ring formula:

In this formula, “N²” or “N2” references the 2-amino substituent, whichis a site for possible reaction (e.g., acylation or diacylation). Insome embodiments, a 2-aminoimidazole may be a tautomeric form of generalring formula:

In some aspects of the present application's invention, the ringsubstituents are as otherwise defined herein (e.g., one of the R groupsis acyl; claim 1; and the like).

The term “aroyl” as used herein includes an aryl-CO— group wherein arylis as defined herein. Examples include, but are not limited to, benzoyl,naphth-1-oyl and naphth-2-oyl.

The term “aryl” as used herein includes cyclic aromatic carbon ringsystems containing from 6 to 18 carbons. Examples of an aryl groupinclude, but are not limited to, phenyl, naphthyl, anthracenyl,tetracenyl, biphenyl and phenanthrenyl.

An aryl group can be unsubstituted or optionally substituted. Whenoptionally substituted, one or more hydrogen atoms of the aryl group(e.g., from 1 to 5, from 1 to 2, or 1) may be replaced with a moietyindependently selected from the group including alkyl, cyano, acyl,halo, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, andalkylthio.

As used herein, the terms “arylalkyl” and “aralkyl,” which are usedinterchangeably, include an alkyl group as defined herein where at leastone hydrogen substituent has been replaced with an aryl group as definedherein. Examples include, but are not limited to, benzyl, 1-phenylethyl,4-methylbenzyl, and 1,1,-dimethyl-1-phenylmethyl.

As used herein, the term “catalyst” refers to a substance thatparticipates in a chemical reaction so as to increase the rate of thereaction, but that is itself not consumed in the reaction. Examples ofcatalysts include, but are not limited to, metals, metal oxides, metalcomplexes, acids, and bases.

A group can be unsubstituted or optionally substituted as per itscomponent parts. For example, but without limitation, the aryl group ofan arylalkyl group can be substituted, such as in the arylalkyl group4-methylbenzyl. In some preferred embodiments, a group includes at mostthree independently selected optional substituents, and thesesubstituents do no include further optional substituents. In someembodiments, a group includes at most three independently selectedoptional substituents, but these substituents include further optionalsubstituents.

The linking term “comprising” or “comprise” as used herein is notclosed. For example, “a composition comprising A” must include at leastthe component A, but it may also include one or more other components(e.g., B; B and C; B, C, and D; and the like).

The term “cycloalkyl” as used herein includes a cyclic hydrocarbon groupthat may contain an indicated number of carbon atoms: For example,C₃-C₁₂ indicates that the group may have from 3 to 12 (inclusive) carbonatoms in it. If not otherwise indicated, a cycloalkyl group includesabout 3 to about 20 carbon atoms. In some aspects, cyclo alkyl groupshave 3 to about 12 carbon atoms in the group. In other aspects,cycloalkyl groups have 3 to about 7 carbon atoms in the group. Examplesmay include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 4,4-dimethylcyclohexyl, and cycloheptyl.

A cycloalkyl group can be unsubstituted or optionally substituted. Whenoptionally substituted, one or more hydrogen atoms of the cycloalkylgroup (e.g., from 1 to 4, from 1 to 2, or 1) may be replaced with amoiety independently selected from the group including fluoro, hydroxy,alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In someaspects, a substituted cycloalkyl group can incorporate an exo- orendocyclic alkene (e.g., cyclohex-2-en-1-yl).

The terms “disorder,” “disease,” and “condition” are used hereininterchangeably for a condition in a subject. A disorder is adisturbance or derangement that affects the normal function of the bodyof a subject. A disease is a pathological condition of an organ, a bodypart, or a system resulting from various causes, such as infection,genetic defect, or environmental stress that is characterized by anidentifiable group of symptoms.

The term “effective amount” or “effective dose” as used herein includesan amount sufficient to achieve the desired result and accordingly willdepend on the ingredient and its desired result. Nonetheless, once thedesired effect is identified, determining the effective amount is withinthe skill of a person skilled in the art.

As used herein, “fluoroalkyl” includes an alkyl group wherein the alkylgroup includes one or more fluoro-substituents. Examples include, butare not limited to, trifluoromethyl.

As used herein, “geminal” substitution includes two or more substituentsthat are directly attached to the same atom. An example is 3,3-dimethylsubstitution on a cyclohexyl or spirocyclohexyl ring.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, oriodo. In some aspects, “halo” includes fluoro or chloro.

The term “heteroaryl” includes mono and bicyclic aromatic groups ofabout 4 to about 14 ring atoms (e.g., 4 to 10 or 5 to 10 atoms)containing at least one heteroatom. Heteroatom as used in the termheteroaryl refers to oxygen, sulfur and nitrogen. A nitrogen atom of aheteroaryl is optionally oxidized to the corresponding N-oxide. Examplesinclude, but are not limited to, pyrazinyl, furanyl, thienyl, pyridyl,pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl,furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl,pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, and benzothiazolyl.

A heteroaryl group can be unsubstituted or optionally substituted. Insome aspects, when optionally substituted, one or more hydrogen atoms ofthe heteroaryl group (e.g., from 1 to 5, from 1 to 2, or 1) may bereplaced with a moiety independently selected from the group includingalkyl, cyano, acyl, halo, hydroxy, alkoxy, amino, alkylamino, acylamino,thio, and alkylthio.

The term “heteroaroyl” as used herein includes a heteroaryl-C(O)— groupwherein heteroaryl is as defined herein. Heteroaroyl groups include, butare not limited to, thiophenoyl, nicotinoyl, pyrrol-2-ylcarbonyl, andpyridinoyl.

The term “heterocycloyl” as used herein includes a heterocyclyl-C(O)—group wherein heterocyclyl is as defined herein. Examples include, butare not limited to, N-methyl prolinoyl and tetrahydrofuranoyl.

As used herein, “heterocyclyl” includes a non-aromatic saturatedmonocyclic or multicyclic ring system of about 4 to about 10 ring atoms(e.g., 5 to about 8 ring atoms, or 5 to about 6 ring atoms), in whichone or more of the atoms in the ring system is an element or elementsother than carbon, e.g., nitrogen, oxygen or sulfur. A heterocyclylgroup optionally comprises at least one sp²-hybridized atom (e.g., aring incorporating an carbonyl, endocyclic olefin, or exocyclic olefin).In some embodiments, a nitrogen or sulfur atom of the heterocyclyl isoptionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Examples of monocycylic heterocyclyl rings include, but arenot limited to, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.

A heterocycyl group can be unsubstituted or optionally substituted. Whenoptionally substituted, one or more hydrogen atoms of the group (e.g.,from 1 to 4, from 1 to 2, or 1) may be replaced with a moietyindependently selected from the group including fluoro, hydroxy, alkoxy,amino, alkylamino, acylamino, thio, and alkylthio. In some aspects, asubstituted heterocycyl group can incorporate an exo- or endocyclicalkene.

The term “hydrophobic moiety” or “hydrophobic group” as used hereinincludes a moiety or a functional group that repels water. Examples mayinclude, but are not limited to, a non-polar moiety, such as anunsubstituted alkyl group having more than five carbons, phenyl groupand an anthracenyl group.

As used herein, the terms “hydrophilic moiety” or “hydrophilic group”includes a moiety or a functional group that has a strong affinity towater. Examples may include, but are not limited to, a charged moiety,such as cationic moiety and anionic moiety, or a polar uncharged moiety,such as an alkoxy group and amine group.

As used herein, the term “hydroxyalkyl” includes an alkyl group where atleast one hydrogen substituent has been replaced with an alcohol (—OH)group. In certain aspects, the hydroxyalkyl group has one alcohol group.In certain aspects, the hydroxyalkyl group has one or two alcoholgroups, each on a different carbon atom. In certain aspects, thehydroxyalkyl group has 1, 2, 3, 4, 5, or 6 alcohol groups. Examples mayinclude, but are not limited to, hydroxymethyl, 2-hydroxyethyl, and1-hydroxyethyl.

When any two substituent groups or any two instances of the samesubstituent group are “independently selected” from a list ofalternatives, the groups may be the same or different. For example, ifR^(a) and R^(b) are independently selected from the group includingalkyl, fluoro, amino, and hydroxyalkyl, then a molecule with two R^(a)groups and two R^(b) groups could have all groups be alkyl group (e.g.,four different alkyl groups). Alternatively, the first R^(a) could bealkyl, the second R^(a) could be fluoro, the first R^(b) could behydroxyalkyl, and the second R^(b) could be amino (or any othersubstituents taken from the group). Alternatively, both R^(a) and thefirst R^(b) could be fluoro, while the second R^(b) could be alkyl(i.e., some pairs of substituent groups may be the same, while otherpairs may be different).

As used herein, “or” should in general be construed non-exclusionarily.For example, an embodiment of “a composition comprising A or B” wouldtypically present one or more aspects with a composition comprising bothA and B. “Or” should, however, be construed to exclude those aspectspresented that cannot be combined without contradiction (e.g., acomposition pH that is between 9 and 10 or between 7 and 8).

As used herein, the term “salt” refers to acid or base salts of acompound, e.g., ZNA or another 2-(acylamino)imidazole. Illustrativeexamples of pharmaceutically acceptable salts are cationic salts such asalkali and alkaline earth metal (such as sodium, lithium, potassium,calcium, and magnesium) salts, ammonium (ammonium, trimethyl ammonium,diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium) salts,mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, andthe like) salts, organic carboxylic acid (acetic acid, propionic acid,glutamic acid, citric acid, and the like) salts, organic sulfonic acid(methanesulfonic acid) salts, and quaternary ammonium (methyl iodide,ethyl iodide, and the like) salts. Additional information on suitablepharmaceutically acceptable salts can be found in Remington's,Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton,Pa., which is incorporated herein by reference.

The terms “a salt thereof,” “salt thereof,” or “salts thereof” can beapplied to any preceding member of an associated Markush group. Forexample, a group consisting of A, B, C, and salts thereof would includewithin its scope embodiments that were a salt of A, embodiments thatwere a salt of B, and embodiments that were a salt of C.

As used herein, “spirocycloalkyl” as used herein includes a cycloalkylin which geminal substituents on a carbon atom are replaced to join informing a 1,1-substituted ring. For example, but without limitation, fora —C(R¹)(R²)— group that was part of a longer carbon chain, if R¹ and R²joined to form a cyclopropyl ring incorporating the carbon to which R¹and R² were bonded, this would be a spirocycloalkyl group (i.e.,spirocyclopropyl).

As used herein, “spiroheterocyclyl” as used herein includes aheterocycloalkyl in which geminal substituents on a carbon atom arereplaced to join in forming a 1,1-substituted ring. For example, butwithout limitation, for a —C(R¹)(R²)— group that was part of a longercarbon chain, if R¹ and R² joined to form a pyrrolidine ringincorporating the carbon to which R¹ and R² were bonded, this would be aspiroheterocyclyl group.

As used herein, the term “treat,” “treating,” or “treatment” includesadministering or applying a composition (e.g., a composition describedherein) in an amount, manner (e.g., schedule of administration), andmode (e.g., route of administration) that is effective to improve adisorder or a symptom thereof, or to prevent, to retard, or to slow theprogression of a disorder or a symptom thereof. Such improvements caninclude, but are not limited to, alleviation or amelioration of one ormore symptoms or conditions, diminishment of the extent of a disease,stabilizing (i.e., not worsening) the state of disease, prevention of adisease's transmission or spread, delaying or slowing of diseaseprogression, amelioration or palliation of the disease state,diminishment of the reoccurrence of disease, and remission, whetherpartial or total and whether detectable or undetectable.

“Treating” and “treatment” as used herein also include prophylactictreatment. In certain embodiments, treatment methods compriseadministering to a subject a therapeutically effective amount of anactive agent. The administering step may consist of a singleadministration or may comprise a series of administrations. The lengthof the treatment period depends on a variety of factors, such as theseverity of the condition, the age of the patient, the concentration ofactive agent, the activity of the compositions used in the treatment, ora combination thereof. It will also be appreciated that the effectivedosage of an agent used for the treatment or prophylaxis may increase ordecrease over the course of a particular treatment or prophylaxisregime. Changes in dosage may result and become apparent by standarddiagnostic assays known in the art. In some aspects, chronicadministration may be required. For example, the compositions areadministered to the subject in an amount, and for a duration, sufficientto treat the patient.

In the Summary of the Invention above, Detailed Description, and theclaims below, reference is made to particular features and aspects ofthe invention, including method steps. The disclosure of the inventionin this specification includes all possible combinations of suchparticular features within the embodiments of the invention disclosed,at least to the extent that such combinations are non-contradictory. Forexample, if the Detailed Description presents aspects A, B, and C of anembodiment, it is understood that this also discloses particularembodiments including both aspects A and B, both aspects B and C, andboth aspects A and C, as well as an embodiment with aspects A, B, and C.

Compositions

In a first embodiment, the invention presents a 2-(acylamino)imidazolecompound selected from the group including:

or a salt thereof;wherein:

R¹ is a member selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;

X is a member selected from the group consisting of a bond, O, andNR^(5a);

Y is a member selected from the group consisting of O, S, or NR^(5b);or, when X is O or a bond, Y is O;

R² is a member independently selected from the group consisting ofalkyl, alkenyl, alkynyl, and arylalkyl; or, alternatively, R² and R⁷join to form an additional heterocyclyl fused ring;

R⁴ is a member independently selected from the group consisting of aryland heteroaryl, wherein R⁴ has from one to five R^(6a) substituents;

R^(5a) and R^(5b) are each a member independently selected from thegroup consisting of hydrogen, alkyl, fluoroalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, arylalkyl, and heteroarylalkyl;

each of the R^(6n) members is independently selected from the groupconsisting of hydrogen, alkyl, hydroxy, alkoxy, aminoalkoxy, alkylamino,alkylaminoalkoxy, alkenyl, alkynyl, aryl, aryloxy, arylamino,cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkoxy,cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocycyloxy,heterocycylalkyloxy, heterocycylamino, heterocycylalkylamino, halo,haloalkyl, fluoroalkyloxy, arylalkyl, arylalkyloxy, arylalkylamino,heteroaryl, heteroaryloxy, heteroarylamino, heteroarylalkyl,heteroarylalkyloxy, and heteroarylalkylamino; or, alternatively, a pairof adjacent R^(6n) members join to form an additional fused ring that isselected from the group consisting of cycloalkyl, aryl, heterocyclyl,and heterocycloaryl; and

R⁷ is a member independently selected from the group consisting ofhydrogen, halo, trifluoromethyl, and alkyl; or, alternatively, R² and R⁷join to form an additional heterocyclyl fused ring;

wherein the 2-(acylamino)imidazole compound is not a natural product.

In some aspects, if R¹ is aryl, arylalkyl, heteroaryl, orheteroarylalkyl, then R¹ is unsubstituted or optionally substituted withfrom one to five substituents independently selected from the groupconsisting of alkyl, cyano, acyl, halo, hydroxy, alkoxy, amino,alkylamino, acylamino, thio, and alkylthio. In certain aspects, R¹ isunsubstituted.

In some aspects, the invention sets forth the composition describedabove, wherein R⁴ is heteroaryl. In some more specific aspects, the R⁴heteroaryl ring incorporates at least one hydrogen bond acceptorselected from the group including N, O, and S.

In some more specific aspects, the hydrogen bond acceptor is O. In someaspects, R⁴ is furanyl substituted with three independently selectedR^(6n) (e.g., H). In some aspects, R⁴ is oxazolyl substituted with twoindependently selected R^(6n) (e.g., H).

In some more specific aspects, the hydrogen bond acceptor is S. In someaspects, R⁴ is thiophenyl substituted with three independently selectedR^(6n) (e.g., H). In some aspects, R⁴ is thiazolyl substituted with twoindependently selected R^(6n) (e.g., H).

In some preferred more specific aspects, the hydrogen bond acceptor isN. In some aspects, R⁴ is unsubstituted. In some aspects, R⁴ is pyridylsubstituted with four independently selected R^(6n). In some aspects, R⁴is pyrazinyl substituted with three independently selected R^(6n). Insome aspects, R⁴ is pyrimidinyl substituted with three independentlyselected R^(6n). In some aspects, R⁴ is imidazolyl substituted withthree independently selected R^(6n). In some aspects, R⁴ is pyrazolylsubstituted with three independently selected R^(6n). In some aspects,R⁴ is oxazolyl substituted with two independently selected R^(6n). Insome aspects, R⁴ is thiazolyl substituted with two independentlyselected R^(6n).

In some more specific aspects, R⁴ is selected from the group including

In some more specific aspects, A¹ is a hydrogen bond acceptor selectedfrom the group including N, O, and S.

In some more specific aspects, A¹ is a hydrogen bond acceptor N. In somemore specific aspects, A¹ is a hydrogen bond acceptor O. In some morespecific aspects, A¹ is a hydrogen bond acceptor S. As would be apparentto the skilled artisan, a hydrogen bond acceptor has at least oneelectron pair that is suitable for forming a hydrogen bond. In somepreferred aspects, the hydrogen bond acceptor is a Lewis base that issuitable for coordinating a metal ion (e.g., a zinc cation).

In some more specific aspects, A², A³, A⁴, and A⁵ are each independentlyselected from the group including N, O, S, CH, and CR^(6n); with theproviso that R⁴ does not have a formal charge (e.g., when A² in thestructure above is O, it can be A³-O⁰-A¹, but not A³=O⁺¹-A¹ orA³-O⁺¹=A¹). In some aspects, A², A³, A⁴, and A⁵ are each anindependently selected CH or CR^(6n). In some aspects, one of A², A³,A⁴, and A⁵ is selected from the group including N, O, and S, and theremaining A groups are each an independently selected CH or CR^(6n).

In some more specific aspects, R⁴ is selected from the group consistingof pyridyl, pyrazinyl, imidazolyl, pyrazinyl, and oxazoyl. In certainaspects, R⁴ is unsubstituted. In certain aspects, R⁴ has from one tofour R^(6n) substituents.

In some aspects, the 2-aminoimidazole compound is substantially freefrom an impurity selected from the group including

or a salt thereof.In preferred aspects, “substantially free” denotes <2% of the impurity;more preferably, <1% of the impurity; and still more preferably, <0.2%of the impurity.

In some aspects, R¹ is a member selected from the group including alkyl,aryl, arylalkyl, and heteroaryl. In some preferred aspects, if R¹ isaryl, arylalkyl, heteroaryl, or heteroarylalkyl, then R¹ isunsubstituted or optionally substituted with from one to fivesubstituents independently selected from the group consisting of alkyl,cyano, acyl, halo, hydroxy, alkoxy, amino, alkylamino, acylamino, thio,and alkylthio. In some more specific aspects, R¹ is a member selectedfrom the group including isopropyl, sec-butyl, phenyl, 2-bromophenyl,4-chlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2-fluorophenyl,4-fluorophenyl, 4-methoxyphenyl, 3,4-methylenedioxyphenyl,3-trifluoromethylphenyl, and 2-thiazolyisopropyl. In some more specificaspects, R¹ is a member selected from the group including sec-butyl,phenyl, 2-fluorophenyl, 2,4-dichlorophenyl, and 2-thiazolyl. In somemore specific aspects, R¹ is a member selected from the group includingphenyl, 2-fluorophenyl, 3-trifluoromethylphenyl, 4-chlorophenyl,4-methoxyphenyl, and cyclopropyl.

In some aspects, R¹ is alkyl. In some more specific aspects, R¹ ismethyl, ethyl, isopropyl, sec-butyl, or tert-butyl. In some morespecific aspects, R¹ is isopropyl or sec-butyl. In some more specificaspects, R¹ is tert-butyl.

In some aspects, R¹ is alkenyl. In some more specific aspects, R¹ isallyl or methallyl.

In some aspects, R¹ is alkynyl. In some more specific aspects, R¹ ispropargyl.

In some aspects, R¹ is aryl. In some more specific aspects, R¹ isphenyl. In some alternative aspects, R¹ is haloaryl (e.g., halophenyl).In some more specific aspects, R¹ is 2-fluorophenyl or2,4-dichlorophenyl. In some more specific aspects, R¹ is 4-halophenyl(e.g., 4-chlorophenyl).

In some aspects, R¹ is arylalkyl. In some more specific aspects, R¹ isbenzyl.

In some aspects, R¹ is heteroaryl. In some more specific aspects, R¹ is4-1,3-, or 2-pyridyl.

In some aspects, R¹ is heteroarylalkyl. In some more specific aspects,R¹ is 4-1,3-, or 2-pyridylmethyl.

In some preferred aspects, X is a bond. In some alternative aspects, Xis O. In some alternative aspects, X is NR^(5a).

In some aspects, Y is O. In some alternative aspects, Y is NR^(5b).

In some aspects, R⁷ is a member independently selected from the groupincluding hydrogen, halo, trifluoromethyl, and alkyl; or, alternatively,R² and R⁷ join to form an additional heterocyclyl fused ring.

In some aspects, R² is a member selected from the group including alkyl,alkenyl, and arylalkyl. In some aspects, R² is alkyl. In some morespecific aspects, R² is methyl. In some more specific aspects, R² isethyl. In some aspects, R² is allyl.

In some aspects, R² and R⁷ join to form an additional heterocyclyl fusedring. In some aspects, R2 and R7 are linked by —(CR^(3a)R^(3b))_(n)—,wherein n is an integer from 2 to 4 (preferably, 2 or 3); and whereineach R^(3a) and R^(3b) is independently selected from the groupconsisting of hydrogen, lower alkyl, lower fluoroalkyl, alkenyl,alkynyl, and fluoro; or, alternatively, a geminal R^(3a) and R^(3b)combine to form an oxo-group.

In some aspects, R^(5a) and R^(5b) are each a member independentlyselected from the group including hydrogen, alkyl, fluoroalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, and heteroarylalkyl.

In some aspects, A¹, A², A³, A⁴, and A⁵ are each an independentlyselected CH or CR^(6n). In some alternative aspects, only one of A¹, A²,A³, A⁴, and A⁵ is N. In some alternative aspects, only two membersselected from the group including A¹, A², A³, A⁴, and A⁵ are N. In somealternative aspects, only three members selected from the groupincluding A¹, A², A³, A⁴, and A⁵ are N.

In some aspects, each of the R^(6a) members is independently selectedfrom the group including alkyl, hydroxy, alkoxy, aryl, aryloxy,cycloalkyl, cycloalkoxy, cycloalkylalkoxy, heterocyclyl, heterocycyloxy,heterocycylalkyloxy, halo, fluoroalkyl, fluoroalkyloxy, heteroaryl,heteroaryloxy, arylalkyl, arylalkyloxy, arylalkylamino, andheteroarylalkyloxy. In some aspects, each of the R^(6n) members isindependently selected from the group including alkyl, hydroxy, alkoxy,cycloalkylalkoxy, halo, fluoroalkyl, fluoroalkyloxy, and arylalkyloxy.In some aspects, R⁴ is unsubstituted (i.e., hydrogen substitution).

In some aspects, each of the R^(6n) members is independently selectedfrom the group including alkyl, hydroxy, alkoxy, aryl, aryloxy,cycloalkyl, cycloalkoxy, cycloalkylalkoxy, heterocyclyl, heterocycyloxy,halo, fluoroalkyl, fluoroalkyloxy, heteroaryl, heteroaryloxy, arylalkyl,arylalkyloxy, arylalkylamino, and heteroarylalkyloxy. In some aspects,each of the R^(6n) members is independently selected from the groupincluding alkyl, hydroxy, alkoxy, cycloalkylalkoxy, halo, fluoroalkyl,fluoroalkyloxy, and arylalkyloxy. In some aspects, each of the R^(6n)members is independently selected from the group including alkyl,hydroxy, and alkoxy. In some aspects, R⁴ is unsubstituted (i.e.,hydrogen substitution).

In some aspects,

has from one to three hydroxyl or alkyoxy substituents.

In some aspects, A³ is C(OH) or C(OMe). In some alternative aspects, A³is CH, CCl, C(OMe), or

In some aspects, the R⁴ group has one R^(6n) substitutent. In some morespecific aspects, the R⁴ group is bicyclic (e.g., naphthyl; indolyl). Insome still more specific aspects, at least six of the R⁴ substituentsare hydrogen. In some still more specific aspects, at least eight of theR⁴ substituents are hydrogen.

In some aspects, R⁷ is a member independently selected from the groupincluding hydrogen, halo, trifluoromethyl, and alkyl; or, alternatively,R² and R⁷ join to form an additional heterocyclyl fused ring.

In some aspects, R⁷ is alkyl or hydrogen. In some aspects, R⁷ ishydrogen. In some aspects, R⁷ is alkyl (e.g., C₁-C₄ alkyl or C₁-C₃alkyl). In some aspects, R⁷ is methyl. In some aspects, R⁷ is isopropyl.

In some aspects, R⁷ is aminoalkyl or alkylaminoalkyl. In some morespecific aspects, R⁷ is morpholinylmethyl.

In some more specific aspects, the invention sets forth the compositioncomprising a 2-(acylamino)imidazole compound

or a salt thereof.

In some aspects,

is a phenol. In some more specific aspects,

is a p-phenol (e.g., 4-hydroxyphenyl).

In some aspects,

is a phenol. In some more specific aspects,

is a p-phenol (e.g., 4-hydroxyphenyl).

In some aspects, the invention sets forth a compound selected from thosein Table I and salts thereof.

From a structural standpoint, the N-Me-hydantoin derived headgroup ofnaamidine A or a similar compound might well serve as a canonical2-point kinase binder (analogous to a 2-aminopyridine). See Yoon et al.Invest. Ophthalmol. Vis. Sci. 2010; Enzenmuller et al. Anticancer drugs2013, 24 (1), 14-9; Xue et al. PLoS One 2014, 9 (10),e109180/1-e109180/6, 6 pp. The hydantoin headgroup might also serve as ahighly promiscuous binder (similar to the rhodanines and otherhydantoins) contributing to significant “off-target” effects. See Dinget al. Cancer Res. 2005, 65 (8), 3389-3395; Lind et al. Transl. Res.2009, 154 (3), 153-159; Yu et al. Biochem. J 2009, 417 (1), 133-139;Takeda et al. PLoS One 2011, 6 (12), e28615; Jiang et al. Cancer Lett.2011, 312 (1), 11-17; Park et al. Neurobiol. Dis. 2011, 42 (3), 242-51;Cao et al. Sci Rep 2014, 4. Advantageously, these effects should beminimized or avoided in the structurally simpler series ofN²-acyl-2-aminoimidazoles of the claimed invention.

Methods of Treatment

In a second embodiment, the invention presents a method of killingbacteria in vitro, the method comprising treating the bacteria with acomposition set forth in the first embodiment or one of its aspects. Insome alternative aspects of those presented, the invention presents acompound or composition for use in such a method.

In a third embodiment, the invention presents a method of killingbacteria in vivo, the method comprising administering a composition setforth in the first embodiment or one of its aspects to a patient. Insome alternative aspects of those presented, the invention presents acompound or composition for use in such a method.

In a fourth embodiment, the invention presents a method of treatingcancer, the method comprising administering a composition set forth inthe first embodiment or one of its aspects to a patient with cancer,thereby treating the patient. In some alternative aspects of thosepresented, the invention presents a compound or composition for use insuch a method.

Without intending to be bound by theory, the method of action for theinventive compounds and compositions may include modulation of zincmetabolism. Zinc is an essential trace metal. Bioinformatic studies haveestimated that 10% of the proteome may bind zinc, 40% of these proteinsfunctioning as transcription factors and the remaining 60% functioningin an enzymatic or an ion transport capacity (15). Considering theubiquitous nature of the ion and the necessity of zinc for propercellular function, it is not surprising then that perturbations in zinchomeostasis are correlated with varying disease states: Zincaccumulation has been found to occur in conjunction with the formationof Alzheimer's disease-associated extracellular plaques and increasedzinc levels have been observed in malignant breast tissue compared tononmalignant tissue (16-18). Exploiting the differences in zinchomeostasis between healthy and diseased tissue could provide abeneficial treatment window for therapeutics.

In some aspects, the methods of treating cancer comprise the compoundZNA. As the Examples show, ZNA synergizes strongly with Zn²⁺ to inducecancer-selective cell death via a caspase-independent mechanism. ZNA wasfound to be effective against primary metastatic cells derived frombreast cancer patients treated with multiple frontlinechemotherapeutics, and the small molecule's in vivo efficacy wasestablished using a mouse mammary tumor model. Taken together, theExamples suggest that destabilizing Zn²⁺ trafficking pathways andinducing intracellular Zn²⁺ dyshomeostasis are viable mechanisms bywhich to selectively target breast cancer. Furthermore, ZNA's activityagainst chemoresistant patient-derived tumor cells, which model themolecular and genomic characteristics of breast cancer following patienttreatment initiation, suggests that the affected pathways are clinicallyrelevant in vivo.

In some embodiments, the invention presents a composition fortherapeutic use, the composition including a 2-(acylamino)imidazole ofone of the aspects herein. In some aspects, the composition furtherincludes a pharmaceutically acceptable excipient.

In instances where the 2-(acylamino)imidazole compound is to beadministered to a subject, the compounds can be incorporated intopharmaceutical compositions. The 2-(acylamino)imidazole compound can beincorporated into pharmaceutical compositions as pharmaceuticallyacceptable salts or derivatives. Some pharmaceutically acceptablederivatives of the 2-(acylamino)imidazole compounds of the presentinvention may include a chemical group that increases aqueoussolubility. As used herein, a “pharmaceutically acceptable carrier”means a substance that can be administered to a subject together with a2-(acylamino)imidazole compound or salt thereof (i.e., as a carrier), ora combination of a 2-(acylamino)imidazole compound (or salt thereof)with another compound, and that does not destroy the pharmacologicalactivity thereof. Pharmaceutically acceptable carriers include, forexample, solvents, binders, dispersion media, coatings, preservatives,colorants, isotonic and absorption delaying agents, and the like thatare compatible with pharmaceutical administration. Supplementary activecompounds can also be incorporated into the compositions.

Non-limiting examples of pharmaceutically acceptable carriers that canbe used include poly(ethylene-co-vinyl acetate), PVA, partiallyhydrolyzed poly(ethylene-co-vinyl acetate), poly(ethylene-co-vinylacetate-co-vinyl alcohol), a cross-linked poly(ethylene-co-vinylacetate), a cross-linked partially hydrolyzed poly(ethylene-co-vinylacetate), a cross-linked poly(ethylene-co-vinyl acetate-co-vinylalcohol), poly-D,L-lactic acid, poly-L-lactic acid, polyglycolic acid,PGA, copolymers of lactic acid and glycolic acid (PLGA),polycaprolactone, polyvalerolactone, poly(anhydrides), copolymers ofpolycaprolactone with polyethylene glycol, copolymers of polylactic acidwith polyethylene glycol, polyethylene glycol; and combinations andblends thereof.

Other carriers include, e.g., an aqueous gelatin, an aqueous protein, apolymeric carrier, a cross-linking agent, or a combination thereof. Inother instances, the carrier is a matrix. In yet another instances, thecarrier includes water, a pharmaceutically acceptable buffer salt, apharmaceutically acceptable buffer solution, a pharmaceuticallyacceptable antioxidant, ascorbic acid, one or more low molecular weightpharmaceutically acceptable polypeptides, a peptide comprising about 2to about 10 amino acid residues, one or more pharmaceutically acceptableproteins, one or more pharmaceutically acceptable amino acids, anessential-to-human amino acid, one or more pharmaceutically acceptablecarbohydrates, one or more pharmaceutically acceptablecarbohydrate-derived materials, a non-reducing sugar, glucose, sucrose,sorbitol, trehalose, mannitol, maltodextrin, dextrins, cyclodextrin, apharmaceutically acceptable chelating agent, EDTA, DTP A, a chelatingagent for a divalent metal ion, a chelating agent for a trivalent metalion, glutathione, pharmaceutically acceptable nonspecific serum albumin,or combinations thereof.

The route of administration of a therapeutic agent (e.g., atherapeutically active 2-(acylamino)imidazole or a salt thereof) can beoral, intraperitoneal, transdermal, subcutaneous, by intravenous orintramuscular injection, by inhalation, topical, intralesional,infusion; liposome-mediated delivery; topical, intrathecal, gingivalpocket, rectal, intrabronchial, nasal, transmucosal, intestinal, ocularor otic delivery, or any other methods known in the art. In someaspects, the 2-(acylamino)imidazole therapeutic agent or a salt thereofis administered orally, intravenously, or intraperitoneally.

In some aspects, the 2-(acylamino)imidazole therapeutic agent or a saltthereof is administered at a therapeutically effective amount or dose. Adaily dose range of about 0.01 mg/kg to about 500 mg/kg, or about 0.1mg/kg to about 200 mg/kg, or about 1 mg/kg to about 100 mg/kg, or about10 mg/kg to about 50 mg/kg, can be used. The dosages, however, may bevaried according to several factors, including the chosen route ofadministration, the formulation of the composition, patient response,the severity of the condition, the subject's weight, and the judgment ofthe prescribing physician. The dosage can be increased or decreased overtime, as required by an individual patient. In certain instances, apatient initially is given a low dose, which is then increased to anefficacious dosage tolerable to the patient. Determination of aneffective amount is well within the capability of those skilled in theart.

In some aspects, 2-(acylamino)imidazole therapeutic agent or a saltthereof is administered in combination with a second therapeutic agent.In some aspects, the second therapeutic agent is a chemotherapeuticagent. In some aspects, the chemotherapeutic agent is an alkylatingagent (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan,melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, ortemozolomide), an anthracycline (e.g., doxorubicin, adriamycin,daunorubicin, epirubicin, or mitoxantrone), a cytoskeletal disruptor(e.g., paclitaxel or docetaxel), a histone deacetylase inhibitor (e.g.,vorinostat or romidepsin), an inhibitor of topoisomerase (e.g.,irinotecan, topotecan, amsacrine, etoposide, or teniposide), a kinaseinhibitor (e.g., bortezomib, erlotinib, gefitinib, imatinib,vemurafenib, or vismodegib), a nucleoside analog or precursor analog(e.g., azacitidine, azathioprine, capecitabine, cytarabine,fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, orthioguanine), a peptide antibiotic (e.g., actinomycin or bleomycin), aplatinum-based agent (e.g., cisplatin, oxaloplatin, or carboplatin), ora plant alkaloid (e.g., vincristine, vinblastine, vinorelbine,vindesine, podophyllotoxin, paclitaxel, or docetaxel). In some aspects,the chemotherapeutic agent is gemcitabine.

Co-administered therapeutic agents (e.g., a 2-(acylamino)imidazoletherapeutic agent or a salt thereof, and a second therapeutic agent asdescribed herein) can be administered together or separately,simultaneously or at different times. When administered, the therapeuticagents independently can be administered once, twice, three, or fourtimes daily, or more or less often, as needed. In some aspects, theadministered therapeutic agents are administered once daily. In someaspects, the administered therapeutic agents are administered at thesame time or times, for instance as an admixture. In some aspects, oneor more of the therapeutic agents is administered in a sustained-releaseformulation.

In some aspects, an 2-(acylamino)imidazole therapeutic agent or a saltthereof, and a second therapeutic agent are administered concurrently.In some aspects, the 2-(acylamino)imidazole therapeutic agent or saltthereof is administered first, for example for about 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100 days or moreprior to administering the second therapeutic agent (e.g.,chemotherapeutic agent). In some aspects, the second therapeutic agent(e.g., chemotherapeutic agent) is administered first, for example forabout 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80,90, 100 days or more prior to administering the 2-(acylamino)imidazoletherapeutic agent or salt thereof.

In some aspects, a 2-(acylamino)imidazole therapeutic agent or a saltthereof (and optionally a second therapeutic agent, e.g., achemotherapeutic agent as described herein) is administered to thesubject over an extended period of time, e.g., for at least 30, 40, 50,60, 70, 80, 90, 100, 150, 200, 250, 300, 350 days or longer.

In other aspects, compositions and kits for use in treating orpreventing a cancer in a subject are provided.

In some aspects, compositions and kits for treating a cancer areprovided. In some embodiments, the composition or kit comprises:

a composition set forth in the first embodiment or one of its aspects.

In some aspects, pharmaceutical compositions comprising a2-(acylamino)imidazole therapeutic agent or a salt thereof, for use inadministering to a subject having a cancer are provided. In someaspects, the 2-(acylamino)imidazole therapeutic agent or salt thereof isas described above. In some aspects, a 2-(acylamino)imidazoletherapeutic agent or a salt thereof, and a second therapeutic agent(e.g., a chemotherapeutic agent as described herein) are formulated intopharmaceutical compositions, together or separately, by formulation withappropriate pharmaceutically acceptable carriers or diluents, and can beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, pills, powders, granules, dragees,gels, slurries, ointments, solutions, suppositories, injections,inhalants and aerosols.

Guidance for preparing formulations for use in the present invention isfound in, for example, in Remington: The Science and Practice ofPharmacy, 21^(st) Ed., 2006, supra; Martindale: The Complete DrugReference, Sweetman, 2005, London: Pharmaceutical Press; Niazi, Handbookof Pharmaceutical Manufacturing Formulations, 2004, CRC Press; andGibson, Pharmaceutical Preformulation and Formulation: A Practical Guidefrom Candidate Drug Selection to Commercial Dosage Form, 2001,Interpharm Press, which are hereby incorporated herein by reference. Thepharmaceutical compositions described herein can be manufactured in amanner that is known to those of skill in the art, i.e., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or lyophilizing processes. Thefollowing methods and excipients are merely exemplary and are in no waylimiting.

In some aspects, a 2-(acylamino)imidazole therapeutic agent or a saltthereof (and optionally a second therapeutic agent, e.g, achemotherapeutic agent as described herein) is prepared for delivery ina sustained-release, controlled release, extended-release, timed-releaseor delayed-release formulation, for example, in semi-permeable matricesof solid hydrophobic polymers containing the therapeutic agent. Varioustypes of sustained-release materials have been established and are wellknown by those skilled in the art. Current extended-release formulationsinclude film-coated tablets, multiparticulate or pellet systems, matrixtechnologies using hydrophilic or lipophilic materials and wax-basedtablets with pore-forming excipients (see, for example, Huang, et al.Drug Dev. Ind. Pharm. 29:79 (2003); Pearnchob, et al. Drug Dev. Ind.Pharm. 29:925 (2003); Maggi, et al. Eur. J. Pharm. Biopharm. 55:99(2003); Khanvilkar, et al., Drug Dev. Ind. Pharm. 228:601 (2002); andSchmidt, et al., Int. J. Pharm. 216:9 (2001)). Sustained-releasedelivery systems can, depending on their design, release the compoundsover the course of hours or days, for instance, over 4, 6, 8, 10, 12,16, 20, 24 hours or more. Usually, sustained release formulations can beprepared using naturally-occurring or synthetic polymers, for instance,polymeric vinyl pyrrolidones, such as polyvinyl pyrrolidone (PVP);carboxyvinyl hydrophilic polymers; hydrophobic and/or hydrophilichydrocolloids, such as methylcellulose, ethylcellulose,hydroxypropylcellulose, and hydroxypropylmethylcellulose; andcarboxypolymethylene.

For oral administration, a 2-(acylamino)imidazole therapeutic agent or asalt thereof (and optionally a second therapeutic agent, e.g, achemotherapeutic agent as described herein) can be formulated readily bycombining with pharmaceutically acceptable carriers that are well knownin the art. Such carriers enable the compounds to be formulated astablets, pills, dragees, capsules, emulsions, lipophilic and hydrophilicsuspensions, liquids, gels, syrups, slurries, suspensions and the like,for oral ingestion by a patient to be treated. Pharmaceuticalpreparations for oral use can be obtained by mixing the compounds with asolid excipient, optionally grinding a resulting mixture, and processingthe mixture of granules, after adding suitable auxiliaries, if desired,to obtain tablets or dragee cores. Suitable excipients include, forexample, fillers such as sugars, including lactose, sucrose, mannitol,or sorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired,disintegrating agents can be added, such as a cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

The 2-(acylamino)imidazole therapeutic agent or salt thereof (andoptionally a second therapeutic agent, e.g., a chemotherapeutic agent asdescribed herein) can be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Forinjection, the compound or compounds can be formulated into preparationsby dissolving, suspending or emulsifying them in an aqueous ornonaqueous solvent, such as vegetable or other similar oils, syntheticaliphatic acid glycerides, esters of higher aliphatic acids or propyleneglycol; and if desired, with conventional additives such assolubilizers, isotonic agents, suspending agents, emulsifying agents,stabilizers and preservatives. In some aspects, compounds can beformulated in aqueous solutions, preferably in physiologicallycompatible buffers such as Hanks's solution, Ringer's solution, orphysiological saline buffer. Formulations for injection can be presentedin unit dosage form, e.g., in ampules or in multi-dose containers, withan added preservative. The compositions can take such forms assuspensions, solutions or emulsions in oily or aqueous vehicles, and cancontain formulatory agents such as suspending, stabilizing and/ordispersing agents.

The 2-(acylamino)imidazole therapeutic agent or salt thereof (andoptionally a second therapeutic agent, e.g., a chemotherapeutic agent asdescribed herein) can be administered systemically by transmucosal ortransdermal means. For transmucosal or transdermal administration,penetrants appropriate to the barrier to be permeated are used in theformulation. For topical administration, the agents are formulated intoointments, creams, salves, powders and gels. In some aspects, thetransdermal delivery agent can be DMSO. Transdermal delivery systems caninclude, e.g., patches. For transmucosal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art. Exemplary transdermaldelivery formulations include those described in U.S. Pat. Nos.6,589,549; 6,544,548; 6,517,864; 6,512,010; 6,465,006; 6,379,696;6,312,717 and 6,310,177, each of which are hereby incorporated herein byreference.

In some aspects, a pharmaceutical composition comprises an acceptablecarrier and/or excipients. A pharmaceutically acceptable carrierincludes any solvents, dispersion media, or coatings that arephysiologically compatible and that preferably do not interfere with orotherwise inhibit the activity of the therapeutic agent. In someaspects, the carrier is suitable for intravenous, intramuscular, oral,intraperitoneal, transdermal, topical, or subcutaneous administration.Pharmaceutically acceptable carriers can contain one or morephysiologically acceptable compound(s) that act, for example, tostabilize the composition or to increase or decrease the absorption ofthe active agent(s). Physiologically acceptable compounds can include,for example, carbohydrates, such as glucose, sucrose, or dextrans,antioxidants, such as ascorbic acid or glutathione, chelating agents,low molecular weight proteins, compositions that reduce the clearance orhydrolysis of the active agents, or excipients or other stabilizersand/or buffers. Other pharmaceutically acceptable carriers and theirformulations are well-known and generally described in, for example,Remington: The Science and Practice of Pharmacy, 21st Edition,Philadelphia, Pa. Lippincott Williams & Wilkins, 2005. Variouspharmaceutically acceptable excipients are well-known in the art and canbe found in, for example, Handbook of Pharmaceutical Excipients (5^(th)ed., Ed. Rowe et al., Pharmaceutical Press, Washington, D.C.).

In some aspects, kits for use in administering to a subject having acancer are provided. In some aspects, the kit comprises:

a 2-(acylamino)imidazole therapeutic agent or a salt thereof; and

a second therapeutic agent.

In some aspects, the 2-(acylamino)imidazole therapeutic agent or saltthereof is as described above. In some aspects, the second therapeuticagent is a chemotherapeutic agent. In some aspects, the chemotherapeuticagent is an alkylating agent, an anthracycline, a cytoskeletaldisruptor, a histone deacetylase inhibitor, an inhibitor oftopoisomerase, a kinase inhibitor, a nucleoside analog or precursoranalog, a peptide antibiotic, a platinum-based agent, or a plantalkaloid. In some aspects, the chemotherapeutic agent is a nucleosideanalog.

In some aspects, the kits can further comprise instructional materialscontaining directions (i.e., protocols) for the practice of the methodsof this invention. While the instructional materials typically comprisewritten or printed materials they are not limited to such. Any mediumcapable of storing such instructions and communicating them to an enduser is contemplated by this invention. Such media include, but are notlimited to electronic storage media (e.g., magnetic discs, tapes,cartridges, chips), optical media (e.g., CD ROM), and the like. Suchmedia may include addresses to internet sites that provide suchinstructional materials.

For biological methods, specific immunological binding of an antibody toa protein can be detected directly or indirectly. Direct labels includefluorescent or luminescent tags, metals, dyes, radionuclides, and thelike, attached to the antibody. An antibody labeled with iodine-125(¹²⁵I) can be used. A chemiluminescence assay using a chemiluminescentantibody specific for the protein marker is suitable for sensitive,non-radioactive detection of protein levels. An antibody labeled withfluorochrome is also suitable. Examples of fluorochromes include,without limitation, DAPI, fluorescein, Hoechst 33258, R-phycocyanin,B-phycoerythrin, R-phycoerythrin, rhodamine, Texas red, and lissamine.Indirect labels include various enzymes well known in the art, such ashorseradish peroxidase (HRP), alkaline phosphatase (AP),β-galactosidase, urease, and the like. A horseradish-peroxidasedetection system can be used, for example, with the chromogenicsubstrate tetramethylbenzidine (TMB), which yields a soluble product inthe presence of hydrogen peroxide that is detectable at 450 nm. Analkaline phosphatase detection system can be used with the chromogenicsubstrate p-nitrophenyl phosphate, for example, which yields a solubleproduct readily detectable at 405 nm. Similarly, a β-galactosidasedetection system can be used with the chromogenic substrateo-nitrophenyl-β-D-galactopyranoside (ONPG), which yields a solubleproduct detectable at 410 nm. A urease detection system can be used witha substrate such as urea-bromocresol purple (Sigma Immunochemicals; St.Louis, Mo.).

A signal from the direct or indirect label can be analyzed, for example,using a spectrophotometer to detect color from a chromogenic substrate;a radiation counter to detect radiation such as a gamma counter fordetection of ¹²⁵I; or a fluorometer to detect fluorescence in thepresence of light of a certain wavelength. For detection ofenzyme-linked antibodies, a quantitative analysis can be made using aspectrophotometer such as an EMAX Microplate Reader (Molecular Devices;Menlo Park, Calif.) in accordance with the manufacturer's instructions.If desired, the assays of the present invention can be automated orperformed robotically, and the signal from multiple samples can bedetected simultaneously. In some aspects, the amount of signal can bequantified using an automated high-content imaging system. High-contentimaging systems are commercially available (e.g., ImageXpress, MolecularDevices Inc., Sunnyvale, Calif.).

Antibodies can be immobilized onto a variety of solid supports, such asmagnetic or chromatographic matrix particles, the surface of an assayplate (e.g., microtiter wells), pieces of a solid substrate material ormembrane (e.g., plastic, nylon, paper), and the like. An assay strip canbe prepared by coating the antibody or a plurality of antibodies in anarray on a solid support. This strip can then be dipped into the testsample and processed quickly through washes and detection steps togenerate a measurable signal, such as a colored spot.

Analysis of nucleic acid expression levels or genotype can be achievedusing routine techniques such as Southern analysis,reverse-transcriptase polymerase chain reaction (RT-PCR), or any othermethods based on hybridization to a nucleic acid sequence that iscomplementary to a portion of the coding sequence of interest (e.g.,slot blot hybridization) are also within the scope of the presentinvention. Applicable PCR amplification techniques are described in,e.g., Ausubel et al. and Innis et al., supra. General nucleic acidhybridization methods are described in Anderson, “Nucleic AcidHybridization,” BIOS Scientific Publishers, 1999. Amplification orhybridization of a plurality of nucleic acid sequences (e.g., genomicDNA, mRNA or cDNA) can also be performed from mRNA or cDNA sequencesarranged in a microarray. Microarray methods are generally described inHardiman, “Microarrays Methods and Applications: Nuts & Bolts,” DNAPress, 2003; and Baldi et al., “DNA Microarrays and Gene Expression:From Experiments to Data Analysis and Modeling,” Cambridge UniversityPress, 2002.

Analysis of nucleic acid expression levels or genotype can also beperformed using techniques known in the art including, withoutlimitation, microarrays, polymerase chain reaction (PCR)-based analysis,sequence analysis, and electrophoretic analysis. A non-limiting exampleof a PCR-based analysis includes a Taqman® allelic discrimination assayavailable from Applied Biosystems. Non-limiting examples of sequenceanalysis include Maxam-Gilbert sequencing, Sanger sequencing, capillaryarray DNA sequencing, thermal cycle sequencing (Sears et al.,Biotechniques, 13:626-633 (1992)), solid-phase sequencing (Zimmerman etal., Methods Mol. Cell Biol., 3:39-42 (1992)), sequencing with massspectrometry such as matrix-assisted laser desorption/ionizationtime-of-flight mass spectrometry (MALDI-TOF/MS; Fu et al., Nat.Biotechnol., 16:381-384 (1998)), pyrosequencing (Ronaghi et al.,Science, 281:363-365 (1998)), and sequencing by hybridization. Chee etal., Science, 274:610-614 (1996); Drmanac et al., Science, 260:1649-1652(1993); Drmanac et al., Nat. Biotechnol., 16:54-58 (1998). Non-limitingexamples of electrophoretic analysis include slab gel electrophoresissuch as agarose or polyacrylamide gel electrophoresis, capillaryelectrophoresis, and denaturing gradient gel electrophoresis. In someaspects, methods for detecting nucleic acid variants include, e.g., theINVADER® assay from Third Wave Technologies, Inc., restriction fragmentlength polymorphism (RFLP) analysis, allele-specific oligonucleotidehybridization, a heteroduplex mobility assay, single strandconformational polymorphism (SSCP) analysis, single-nucleotide primerextension (SNUPE), and pyrosequencing.

A detectable moiety can be used in the assays described herein. A widevariety of detectable moieties can be used, with the choice of labeldepending on the sensitivity required, ease of conjugation with theantibody, stability requirements, and available instrumentation anddisposal provisions. Suitable detectable moieties include, but are notlimited to, radionuclides, fluorescent dyes (e.g., fluorescein,fluorescein isothiocyanate (FITC), Oregon Green™, rhodamine, Texas red,tetrarhodimine isothiocynate (TRITC), Cy3, Cy5, etc.), fluorescentmarkers (e.g., green fluorescent protein (GFP), phycoerythrin, etc.),autoquenched fluorescent compounds that are activated bytumor-associated proteases, enzymes (e.g., luciferase, horseradishperoxidase, alkaline phosphatase, etc.), nanoparticles, biotin,digoxigenin, and the like.

The analysis can be carried out in a variety of physical formats. Forexample, the use of microtiter plates or automation could be used tofacilitate the processing of large numbers of test samples.

Alternatively, for detecting the level of protein or nucleic acidexpression, antibody or nucleic acid probes can be applied to subjectsamples immobilized on microscope slides. The resulting antibodystaining or in situ hybridization pattern can be visualized using anyone of a variety of light or fluorescent microscopic methods known inthe art.

Analysis of the protein or nucleic acid can also be achieved, forexample, by high pressure liquid chromatography (HPLC), alone or incombination with mass spectrometry (e.g., MALDI/MS, MALDI-TOF/MS, tandemMS, etc.).

Methods of Synthesis

In a fifth embodiment, the invention presents a method of selectivelypreparing a 4-substituted imidazole, the method including the steps:

-   -   cyclizing an α-alkylamino ketone and an acyl cyanamide to form a        2-N-acyl imidazolidin-2-imine product; and    -   converting the 2-N-acyl imidazolidin-2-imine to a        2-acylaminoimidazole product; wherein the 2-acylamino product is        substantially free from 1-acyl and 3-acyl regioisomers (e.g.,        <2% or <1% of such products). In some aspects, the cyclization        step comprises an acid catalyst. In some aspects, the conversion        to the 2-acylaminoimidazole comprises elimination of water with        an acid catalyst (e.g., trifluoacetic acid in ethanol). In some        preferred aspects, the 2-acylamino product is substantially free        from N²,N²-diacyl products (e.g., <2% or <1% of such products).

In a sixth embodiment, the invention presents a method of selectivelypreparing a 2-acylamino 4-substituted imidazole, the method comprisingthe steps:

-   -   monoalkylating an α-amino acid, ester, or amide at the α-amino        group;    -   converting the α-alkylamino acid, ester, or amide to an        α-alkylamino ketone;    -   cyclizing the α-alkylamino ketone and an acyl cyanamide to form        a 2-N-acyl imidazolidin-2-imine product; and    -   converting the 2-N-acyl imidazolidin-2-imine to a        2-acylaminoimidazole product; wherein the 2-acylamino product is        substantially free from 1-acyl and 3-acyl regioisomers (e.g.,        <2% or <1% of such products). In some aspects, the cycling step        comprises an acid catalyst. In some preferred aspects, the        2-acylamino product is substantially free from N²,N²-diacyl        products (e.g., <2% or <1% of such products).

In some aspects of the fifth or sixth embodiment, the α-amino group isprotected. In some more specific aspects, the α-amino protecting groupis a carbamate protecting group. In some more specific aspects, the3-N-protecting group is a tert-butyloxycarbonyl (BOC) group. In somemore specific aspects, the 3-N-protecting group is a Cbz group.

In some aspects of the fifth or sixth embodiments, the method furthercomprises the step of deprotecting the α-amino group (e.g., beforecyclization). In some more specific aspects, the method comprises thestep of removing a tert-butyloxycarbonyl (BOC) group with acid (e.g.,trifluoroacetic acid).

In some aspects of the fifth or sixth embodiment, the 2-acylaminoimidazole product is a compound of the first embodiment or any of itsaspects.

The cyclization reaction in the methods of the invention can beconducted at any suitable temperature. In general, reactions areconducted at temperatures ranging between about 10° C. and about 200° C.A reaction can be conducted, for example, at from about 10° C. to about100° C., or from about 10° C. to about 40° C., or from about 15° C. toabout 150° C., or from about 15° C. to about 35° C., or from about 15°C. to about 25° C. A reaction can be conducted at temperature less thanabout 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, or 155° C. Otherreaction temperatures can be used in the methods of the invention,depending in part on the particular compound used for the cyclizationreaction.

Any suitable solvent or combination of solvents can be used in themethods of the invention. Suitable solvents include, but are not limitedto, ethanol, methanol, diethyl ether, diisopropyl ether, ethyl acetate,benzene, toluene, chloroform, dichloromethane, carbon tetrachloride,1,2-dichloroethane, 1,1-dichloroethane, N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide, N-methyl 2-pyrrolidone, methylethyl ketone, methyl isobutylketone, acetonitrile, propionitrile,1,4-dioxane, sulfolane, 1,2-dimethyoxyethane, and combinations thereof.In some embodiments, the reaction mixture comprises ethanol.

In some embodiments, the reaction mixture comprises an acid catalyst.Suitable acid catalysts include trifluoroacetic acid, hydrochloric acid,hydrobromic acid, trichloroacetic acid, and the like.

Any suitable reaction time can be used in the methods of the invention.In general, reactions are allowed to run for a time sufficient forconsumption of the starting material and conversion to the desiredproduct, or until conversion of the starting material comes to a stop.Reactions are typically allowed to run for any amount of time rangingfrom a few minutes to several hours. Reactions can be run, for example,for anywhere between 5 minutes and 48 hours. Reactions can be run forabout 20 minutes, or about 40 minutes, or about 60 minutes. Reactionscan be run for about 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7,7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 14, 16, 18, 20, 22, 24, 30, 36, 42, or48 hours. In some embodiments, reactions are run for less than 24 hours.In some embodiments, reactions are run for less than 12 hours. In someembodiments, reactions are run for less than 10 hours. Other reactiontimes can be used in the methods of the invention, depending on theparticular catalysts or reactants that are used.

While simple in design, it is very difficult to selectively acylate2-aminoimidazoles. Zhang et al. Eur J Med Chem 2014, 83, 74-83.Predominance of the imino-tautomer initiates N²-acylation over theexpected N³-acylation, and with a product acidified by the acyl group,the second acylation event is facile leading to the diacylated products.In some aspects of the present invention, a regioselective cyclizationwas employed to achieve selectivity.

The compounds in the tables below were made using the methods set forthherein:

TABLE I Selected 2-(Acylamino)imidazoles Com- pound Chemical StructureZNA (for refer- ence)

63

64

65

67

78

79

80

81

82

83

84

85

86

87

96

97

98

99

100

103

104

105

109

110

111

114

119

120

124

128

129

132

133

136

137

138

139

140

141

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

EXAMPLES Example 1: Preparation of Weinreb Amides

General Procedure A: Preparation of Weinreb Amides tert-Butyl(2-(methoxy(methyl)amino)-2-oxoethyl)(methyl)carbamate (1a)

In a 250 mL round bottom flask containing a magnetic stir bar were addedBoc-sarcosine (4.35 g, 22.99 mmol) and CH₂Cl₂ (80 mL) at roomtemperature. Carbonyl diimidazole (4.10 g, 25.29 mmol) was then added inportions over 15 minutes. After 1.5 h, N,O-dimethylhydroxylaminehydrochloride (2.47 g, 25.29 mmol) was added in one portion and thereaction mixture was allowed to stir for an additional 16 h. The mixturewas then diluted with EtOAc (200 mL), and washed consecutively with 1MHCl (100 mL), saturated NaHCO₃(100 mL), and brine (100 mL). The organicextract was dried over Na₂SO₄, filtered, and then evaporated underreduced pressure to yield a colorless oil (4.59 g, 86%). R_(f)=0.33 (6:4hexanes/EtOAc). ¹H NMR (CDCl₃, 500 MHz): δ 4.15 (s, 1.2H, rotamer 1),4.07 (s, 0.8H, rotamer 2), 3.71-3.69 (2s, 3H, rotamer 1 and 2),3.19-3.18 (2s, 3H, rotamer 1 and 2), 2.93-2.92 (2s, 3H, rotamer 1 and2), 1.47 (s, 5.4H, rotamer 1), 1.43 (s, 3.6H, rotamer 2). ¹³C NMR (125MHz, CDCl₃, mixture of rotamers) δ 170.0, 156.3, 155.7, 79.7, 79.6,61.2, 61.2, 50.1, 49.6, 35.8, 35.6, 32.1, 28.3, 28.2, 28.1 ppm. IR (thinfilm) 2976, 2249, 1676, 1479, 1447, 1388, 1366, 1322, 1241, 1175, 1148,1057, 999, 963, 911, 882, 772, 727 cm⁻¹. HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C₁₀H₂₀N₂O₄Na 255.1318; Found 255.1336.

tert-Butyl (1-(methoxy(methyl)amino)-1-oxo-3-phenylpropan-2-yl)(methyl)carbamate (1b)

Prepared according to general procedure A fromN-(tert-butoxycarbonyl)-N-methylphenylalanine (2.0 g, 7.16 mmol),carbonyldiimidazole (1.23 g, 7.88 mmol), and dimethylhydroxylaminehydrochloride (768 mg, 7.88 mmol) as a colorless oil (2.13 g, 92%).R_(f)=0.47 (6:4 hexanes/EtOAc). ¹H NMR (500 MHz, CDCl₃, mixture ofrotamers) δ 7.31-7.07 (m, 5H, rotamers 1 & 2), 5.52 (s, 0.44H, rotamer1), 5.15 (s, 0.66H, rotamer 2), 3.61-3.58 (m, 3H, rotamers 1 & 2),3.16-3.13 (m, 3H, rotamers 1&2), 3.04-2.87 (m, 2H, rotamers 1 & 2),2.83-2.82 (m, 3H, rotamers 1 & 2), 1.32 (s, 4.3H, rotamer 1), 1.21 (s,4.7H, rotamer 2) ppm. ¹³C NMR (125 MHz, CDCl₃, mixture of rotamers) δ171.9, 171.4, 155.6, 154.9, 1380, 137.4, 129.3, 129.2, 128.4, 128.2,126.4, 126.3, 79.8, 79.6, 61.3, 57.1, 54.7, 34.9, 32.3, 30.2, 29.7,28.2, 28.0 ppm. IR (thin film) 2975, 2935, 2245, 1667, 1477, 1454, 1392,1366, 1322, 1254, 1168, 1141, 1076, 991, 958, 909, 865, 721 cm⁻¹. HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for C₁₇H₂₆N₂O₄Na 345.1790; Found 345.1790.

tert-Butyl (1-(methoxy(methyl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate (1c)

Prepared according to general procedure A fromN-(tert-butoxycarbonyl)-N-methylvaline (7.89 g, 34.1 mmol),carbonyldiimidazole (6.08 g, 37.51 mmol), and dimethylhydroxylaminehydrochloride (3.66 g, 37.51 mmol) as a colorless oil (7.95 g, 85%).

tert-Butyl ethyl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (1d)

Prepared according to general procedure A fromN-(tert-butoxycarbonyl)-N-ethylglycine (0.60 g, 3.00 mmol),carbonyldiimidazole (0.53 g, 3.30 mmol), and dimethylhydroxylaminehydrochloride (0.32 g, 3.30 mmol) as a pale yellow oil (0.69 g, 90%); ¹HNMR (500 MHz, CDCl₃, mixture of rotamers): δ 4.14 (s, 2H, rotamer 1),4.05 (s, 1H, rotamer 2), 3.74-3.69 (m, 3H, rotamers 1 & 2), 3.35-3.26(m, 2H, rotamers 1 & 2), 3.18 (s, 3H, rotamers 1 & 2), 1.48 (s, 6H,rotamer 1), 1.43 (s, 3H, rotamer 2), 1.12-1.10 (m, 3H, rotamers 1 &2)ppm. ¹³C NMR (125 MHz, CDCl₃) δ 166.4, 152.1, 151.3, 75.7, 57.4, 43.8,43.5, 39.4, 38.9, 28.6, 24.5, 24.4, 9.6, 9.3 ppm. IR (thin film) 2973,1681, 1400, 1250, 1146, 998, 982, 771 cm⁻¹. HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C₁₁H₂₂N₂O₄Na 269.1477; Found 269.1499.

tert-Butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (1e)

Prepared according to general procedure A from Boc-proline (5.0 g, 23.2mmol), carbonyldiimidazole (4.14 g, 25.5 mmol), anddimethylhydroxylamine hydrochloride (2.48 g, 25.5 mmol) as a colorlessoil (5.16 g, 86%). R_(f)=0.24 (6:4 hexanes/EtOAc). ¹H NMR (500 MHz,CDCl₃, mixture of rotamers) δ 4.75-4.64 (m, 0.45H, rotamer 1), 4.61-4.58(m, 0.55H, rotamer 2), 3.78 (s, 1.4H, rotamer 1), 3.71 (s, 1.6H, rotamer2), 3.65-3.51 (m, 1H, rotamers 1 & 2), 3.48-3.39 (m, 1H, rotamers 1 &2),3.19 (s, 3H), 2.32-2.07 (m, 1H, rotamers 1 & 2), 2.04-1.77 (m, 2H,rotamers 1 & 2), 1.45 (s, 4.4H, rotamer 1), 1.41 (s, 4.6H, rotamer 2)ppm. ¹³C NMR (125 MHz, CD₃OD, mixture of rotamers) δ 191.9, 165.2,131.3, 125.3, 114.1, 62.8, 54.9 (2), 46.0, 29.8, 23.8 ppm. IR (thinfilm) 2974, 1694, 1389, 1160, 1119, 998, 773 cm⁻¹. HRMS (ESI-TOF) m/z:[M+Na]+ Calcd for C₁₂H₂₂N₂O₄Na 281.1477; Found 281.1502.

Example 2: General Procedure B1 (Synthesis of α-Aminoketones)

tert-Butyl methyl(2-oxo-2-phenylethyl)carbamate (2a)

To a cooled solution of (1a) (500 mg, 2.15 mmol) in THF (15 mL) at −10°C. in an oven-dried 50 mL round-bottom flask was added a solution of 3MPhMgBr in ether (1.00 mL, 3.01 mmol). After 1h the reaction mixture wasquenched by dropwise addition of saturated NH₄Cl (5 mL). EtOAc (20 mL)was then added to the solution, and the organic layer was partitioned,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The crude material was purified by column chromatography, eluting with8:2 hexanes/EtOAc to yield a colorless oil (700 mg, 65%). R_(f)=0.52(6:4 hexanes/EtOAc).). ¹H NMR (CDCl₃, 500 MHz): δ 7.95-7.91 (m, 2H,rotamer 1 & 2), 7.61-7.55 (m, 1H, rotamer 1 & 2), 7.50-7.44 (m, 2H,rotamer 1 & 2), 4.67 (s, 1. H, rotamer 1), 4.58 (s, 0.9H, rotamer 2),2.97 (s, 1.4H, rotamer 2), 2.94 (s, 1.6H, rotamer 1), 1.48 (s, 4.8H,rotamer 1), 1.37 (s, 4.2H, rotamer 2). ¹³C NMR (125 MHz, CHCl₃, mixtureof rotamers) δ 191.2, 190.9, 131.3, 129.6, 129.5, 129.5, 126.2, 124.9,124.8, 124.7, 124.5, 124.0, 124.0 (2), 123.8, 120.6, 76.2, 51.7, 51.1,31.7, 25.8, 24.4, 24.3 ppm. IIR (thin film) 2975, 2930, 1686, 1597,1479, 1449, 1390, 1365, 1302, 1224, 1145, 987, 882, 752 cm⁻¹. HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for C₁₅H₂₁NO₄Na 302.1368; Found 302.1374.

tert-Butyl (2-(4-methoxyphenyl)-2-oxoethyl)(methyl)carbamate (2b)

Prepared according to general procedure B1 from4-methoxylphenylmagnesium bromide (1M in THF, 17.25 mL, 17.25 mmol) and1a (3.34 g, 14.4 mmol) as a colorless oil (2.63 g, 55%). R_(f)=0.47 (6:4hexanes/EtOAc). ¹H NMR (CDCl₃, 500 MHz, mixture of rotamers): δ7.96-7.87 (m, 2H, rotamers 1&2), 6.96-6.92 (m, 2H, rotamers 1&2), 4.63(s, 1.1H, rotamer 1), 4.53 (s, 0.9H, rotamer 2), 3.88-3.86 (m, 3H,rotamers 1&2), 2.96-2.93 (m, 2H, rotamers 1&2), 1.48 (s, 5H, rotamer 1),1.37 (s, 4H, rotamer 2). ¹³C NMR (125 MHz, CDCl₃) δ 193.6, 193.2, 163.7,156.3, 130.2, 130.0, 128.3, 113.9, 113.8, 80.0, 79.9, 55.5, 55.3, 54.7,53.4, 35.6, 28.4, 28.2 ppm. IR (thin film) 2974, 2932, 1681, 1600, 1576,1512, 1480, 1455, 1390, 1365, 1308, 1231, 1170, 1141, 1029, 986, 883,834 cm⁻¹. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C₁₅H₂₁NO₄Na 302.1368;Found 302.1374.

tert-Butyl (1-(4-methoxyphenyl)-1-oxo-3-phenylpropan-2-yl)(methyl)carbamate (2c)

Prepared according to general procedure B1 from4-methoxylphenylmagnesium bromide (1M in THF, 14.5 mL, 14.5 mmol) and 1b(3.90 g, 12.1 mmol) as a colorless oil (3.37 g, 75%). R_(f)=0.63 (6:4hexanes/EtOAc). ¹H NMR (500 MHz, CDCl₃, mixture of rotamers) δ 8.03 (d,J=9.0 Hz, 1H, rotamer 1), 7.93 (d, J=9.0 Hz, 1H, rotamer 2), 7.36-7.08(m, 5H, rotamers 1 &2), 6.90-6.88 (m, 2H, rotamers 1 & 2), 5.88 (dd,J=8.8, 6.3 Hz, 0.5H, rotamer 1), 5.43 (dd, J=9.9, 4.7 Hz, 0.5H, rotamer2), 3.84 (d, J=5.1 Hz, 3H, rotamers 1 &2), 3.26-2.93 (m, 2H, rotamers 1& 2), 2.64 (dd, J=17.2, 1.6 Hz, 3H, rotamers 1 &2), 1.30 (dd, J=23.8,1.7 Hz, 9H, rotamers 1 &2) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 196.7, 196.3,163.7, 163.7, 155.3, 154.4, 138.3, 137.7, 131.0, 130.6, 129.5, 129.4,129.3, 128.5, 128.5, 128.4, 128.2, 126.4, 126.4, 126.3, 126.3, 113.8,113.8, 113.7, 80.4, 80.1, 61.9, 59.0, 55.5, 55.4, 55.2, 34.0, 33.9,29.9, 29.7, 28.4, 28.2, 28.2, 28.1 ppm. IR (thin film): 1676, 1599,1512, 1454, 1287, 1366, 1309, 1252, 1165, 1137, 1027 cm⁻¹. HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for C₂₂H₂₇NO₄Na 392.1838; Found 392.1837.

tert-Butyl methyl(3-methyl-1-oxo-1-phenylbutan-2-yl)carbamate (2d)

Prepared according to general procedure B1 from phenylmagnesium bromide(3M in Et₂O, 4.0 mL, 12.0 mmol) and 1c (2.76 g, 10.0 mmol) as acolorless oil (1.25 g, 43%). R_(f)=0.75 (6:4 hexanes/EtOAc). ¹H NMR (500MHz, CDCl₃, mixture of rotamers) δ 8.18-8.11 (m, 1.2H, rotamer 1),8.08-8.00 (m, 0.8H, rotamer 2), 7.63-7.54 (m, 1H, rotamers 1 & 2),7.49-7.45 (m, 2H, rotamers 1 & 2), 5.32 (d, J=10.6 Hz, 0.6H, rotamer 1),5.06 (d, J=10.4 Hz, 0.4H, rotamer 2), 2.67 (s, 1.2H, rotamer 2), 2.62(s, 1.8H, rotamer 1), 2.49-2.39 (m, 1H, rotamers 1 & 2), 1.55 (s, 3H,rotamer 2), 1.45 (s, 5H, rotamer 1), 0.98-0.89 (m, 6H, rotamers 1 & 2).¹³C NMR (126 MHz, CDCl₃, mixture of rotamers) δ 198.1, 197.3, 155.9,155.0, 136.5, 136.2, 133.4, 133.3, 128.7, 128.6, 128.5, 128.5, 127.2,127.2, 80.6, 80.1, 64.0, 62.5, 29.2, 28.5, 28.3, 26.0, 25.8, 20.1, 19.9,18.6, 18.2. IR (thin film) 2970, 2685, 1738, 1677, 1358, 1233, 979, 762cm⁻¹. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C₁₇H₂₅NO₃Na 314.1732; Found314.1735.

tert-Butyl ethyl(2-(4-methoxyphenyl)-2-oxoethyl)carbamate (2e)

Prepared according to general procedure B1 with 1d (0.17 g, 0.69 mmol),4-methoxylphenylmagnesium bromide (1M in THF, 1.38 mL, 1.38 mmol) andanhydrous diethyl ether as solvent. The product was isolated as a yellowoil (0.19 g, quant.). R_(f)=0.5 (3:1 hexanes/EtOAc). ¹H NMR (300 MHz,CDCl₃, mixture of rotamers) δ 7.93 (d, J=8.7 Hz, 2H, rotamer 1),7.28-7.26 (m, 0.4H, rotamer 2), 6.93 (t, J=9.3 Hz, 2H, rotamer 1),6.87-6.84 (m, 0.4H, rotamer 2), 6.79-6.71 (m, 0.8H, rotamer 2), 4.61 (s,1H, rotamer 1), 4.51 (s, 1H, rotamer 2), 3.86 (s, 3H, rotamer 1),3.79-3.73 (m, 1H, rotamer 2), 3.42-3.27 (m, 2H, rotamer 1 & 2), 1.49 (s,5H, rotamer 1), 1.36 (s, 4H, rotamer 2). 1.12-1.09 (m, 3H). ¹³C NMR (125MHz, CDCl₃) δ ¹³C NMR (CDCl₃, 75 MHz): δ 193.9, 163.9, 150.5, 130.5,128.6, 116.2, 114.0, 80.1, 56.0, 53.1, 43.3, 28.7, 13.8. IR (thin film):2976, 2934, 2917, 2849, 1701, 1683, 1602, 1576, 1512, 1480, 1455, 1423,1402, 1366, 1318, 1265, 1233, 1172, 1146, 1113, 832, 779, 733 cm⁻¹.

tert-Butyl ethyl(2-oxo-2-phenylethyl)carbamate (2f)

Prepared according to general procedure B1 with 1d (0.3 g, 1.21 mmol),phenylmagnesium bromide (3M in Et₂O, 0.81 mL, 2.43 mmol) and anhydrousdiethyl ether as solvent. The product was isolated as a yellow oil (0.28g, 88%). R_(f)=0.55 (3:1 hexanes/EtOAc). R_(f)=0.55 (3:1 hexanes/EtOAc);¹H NMR (300 MHz, CDCl₃, mixture of rotamers) δ 7.88-7.87 (m, 2H, rotamer1 & 2), 7.52-7.48 (m, 1H, rotamer 1&2), 7.42-7.35 (m, 2H, rotamer 1 &2), 4.60 (s, 1H, rotamer 1), 4.50 (s, 1H, rotamer 2), 3.34 (q, J=7.0 Hz,1H, rotamer 1), 3.25 (q, J=7.0 Hz, 1H, rotamer 2), 1.43-1.30 (m, 9H,rotamer 1 & 2), 1.06 (t, J=7.0 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ195.2, 156.9, 135.3, 133.4, 128.7, 125.3, 119.4, 115.4, 79.8, 53.3,43.2, 28.3, 13.5.

tert-Butyl 2-(4-methoxybenzoyl)pyrrolidine-1-carboxylate (2 g)

Prepared according to general procedure B1 from 1e (2.5 g, 9.68 mmol)and 4-methoxyphenylmagnesium bromide (2.0 M in THF, 6.8 mL, 13.54 mmol)as an off-yellow solid (850 mg, 29%). R_(f)-0.44 (6:4 hexanes/EtOAc). ¹HNMR (500 MHz, CDCl₃, mixture of rotamers) δ 7.97-7.92 (m, 2H, rotamer 1& 2), 6.95-6.90 (m, 2H, rotamer 1 & 2), 5.29 (dd, J=9.4, 3.0 Hz, 0.4H,rotamer 1), 5.14 (dd, J=8.8, 3.8 Hz, 0.6H, rotamer 2), 3.86 (s, 1.75H,rotamer 2), 3.84 (s, 1.25H, rotamer 1), 3.69-3.41 (m, 2H, rotamers 1 &2), 2.36-2.20 (m, 1H, rotamers 1 & 2), 1.97-1.84 (m, 3H, rotamers 1 &2), 1.45 (s, 4H, rotamer 1), 1.24 (s, 5H, rotamer 2). ¹³C NMR (125 MHz,CDCl₃, mixture of rotamers) δ 197.4, 196.8, 163.5, 154.4, 153.9, 130.8,130.4, 128.2, 128.0, 113.8, 113.7, 79.6, 79.5, 61.0, 60.7, 55.5, 55.4,46.8, 46.6, 31.0, 30.0, 28.5, 28.2, 24.2, 23.6. IR (thin film) 1682,1599, 1575, 1511, 1393, 1365, 1308, 1255, 1230, 1160, 1117, 1027, 990,839 cm⁻¹. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C₁₇H₂₃NO₄Na 328.1525;Found 328.1542.

Example 3: General Procedure B2 (Synthesis of α-Aminoketones)

tert-Butyl (2-(benzo[d][1,3]dioxol-5-yl)-2-oxoethyl)(methyl)carbamate(2h)

To a flame dried 100 mL round-bottom flask under a N₂ atmosphereequipped with a magnetic stir bar was added4-bromo-1-2-methlyenedioxybenzene (1.81 mL, 15 mmol) and freshlydistilled tert-butyl methyl ether (25 mL). The solution was cooled to 0°C., followed by the dropwise addition of 2.5M n-BuLi in hexanes (12 mL,30 mmol) over the period of 15 minutes. The reaction was allowed toproceed for 1 hour at 0° C., and then was cooled to −78° C. A solutionof 1a (3.16 g, 13.6 mmol) dissolved in tert-butyl methyl ether (25 mL)was then added dropwise. The reaction was allowed to warm to roomtemperature overnight, and then was quenched with saturated NH₄Cl (25mL). The suspension was extracted with diethyl ether (2×25 mL), and theorganics were combined, dried over Na₂SO₄, and evaporated under reducedpressure. The crude residue was purified via column chromatography,eluting with a gradient of 9:1 hexanes/EtOAc to 4:1 hexanes/EtOAc toyield a colorless liquid (1.3 g, 33%). R_(f)=0.62 (6:4 hexanes/EtOAc).¹H NMR (500 MHz, CDCl₃, mixture of rotamers) δ 7.60-7.48 (m, 1H, rotamer1 & 2), 7.42 (s, 0.8H, rotamer 1), 7.27 (s, 0.2H, rotamer 2), 6.93-6.65(m, 1H, rotamer 1 & 2), 6.06-6.05 (m, 1H, rotamer 1 & 2), 4.60 (s, 1Hrotamer 1), 4.51 (s, 1H, rotamer 2), 2.96-2.93 (m, 2H, rotamer 1 & 2),1.50 (s, 5H, rotamer 1), 1.39 (s, 4H, rotamer 2) ppm. ¹³C NMR (125 MHz,CDCl₃, mixture of rotamers) δ 193.2, 192.8, 156.3, 155.8, 152.1, 152.0,148.3, 148.2, 144.0, 130.0, 124.1, 123.8, 120.7, 115.2, 108.1, 108.0,107.8, 107.6, 101.9, 101.8, 80.1, 80.0, 55.4, 54.8, 35.7, 35.6, 28.4,28.2 ppm. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C₁₅H₁₉NO₅Na 316.1161;Found 316.1184.

tert-Butyl methyl(2-oxo-2-(o-tolyl)ethyl)carbamate (2i)

Prepared according to general procedure B2 from iodotoluene (1.91 mL,15.0 mmol), nBuLi (2.5M in hexanes, 12 mL, 30.0 mmol), and 1a (3.17 g,13.6 mmol) as a yellow oil (750 mg, 21%). R_(f)=0.54 (6:4hexanes/EtOAc). ¹H NMR (500 MHz, CDCl₃, mixture of rotamers) δ 7.67 (d,J=7.8 Hz, 0.55H, rotamer 1), 7.57 (d, J=7.6 Hz, 0.45H, rotamer 2),7.43-7.38 (m, 1H, rotamer 1 & 2), 7.34-7.19 (m, 2H, rotamer 1 & 2), 4.54(s, 1H, rotamer 1), 4.45 (s, 1H, rotamer 2), 2.98 (s, 1.4H, rotamer 1),2.95 (s, 1.6H, rotamer 2), 2.52-2.51 (m, 3H, rotamer 1 & 2), 1.49 (s,4.2H rotamer 1), 1.42 (s, 5.8H rotamer 2) ppm. ¹³C NMR (125 MHz, CDCl₃,mixture of rotamers) δ 199.3, 198.8, 156.2, 155.7, 138.6, 138.2, 135.9,135.7, 132.1, 132.0, 131.7, 128.2, 127.7, 125.7, 125.6, 78.0, 57.7,57.1, 35.8, 35.7, 28.4, 28.3, 21.1, 20.9, 13.8 ppm.

Example 4: General Procedure B3 (Synthesis of α-Aminoketones)

tert-Butyl methyl(2-oxo-2-(pyridin-2-yl)ethyl)carbamate (2j)

A solution of 2-bromopyridine (3.81 mL, 40.0 mmol) in 15 mL THF wasadded dropwise to a stirring solution of iPrMgCl (2.0 M in THF, 20.0 mL,40.0 mmol) in an oven-dried round bottom flask equipped with a magneticstir bar under N₂ atmosphere at room temperature. The resulting solutionwas allowed to stir overnight. The solution was then cooled to −40° C.,followed by the dropwise addition of 1a (7.3 g, 31.4 mmol) dissolved in15 mL THF. The reaction was then allowed to warm to 0° C., then quenchedupon the addition of saturated NH₄Cl (25 mL). The suspension wasextracted with EtOAc (3×75 mL), and the organics were collected, driedover Na₂SO₄, filtered, and evaporated under reduced pressure. Theresulting crude material was purified via column chromatography, elutingwith a gradient of 4:1 hexanes/EtOAc to 100% EtOAc to yield andoff-yellow solid (4.93 g, 63%). R_(f)=0.58 (6:4 hexanes/EtOAc). ¹H NMR(500 MHz, CDCl₃, mixture of rotamers) δ 8.62 (dd, J=11.3, 4.8 Hz, 1H,rotamers 1 & 2), 7.99 (dd, J=13.5, 7.8 Hz, 1H, rotamers 1 &2), 7.88-7.70(m, 1H, rotamers 1 &2), 7.50-7.36 (m, 1H, rotamers 1 &2), 4.89 (s, 0.9H,rotamer 1), 4.83 (s, 1.1H, rotamer 2), 2.93 (d, J=2.2 Hz, 3H, rotamers 1& 2), 1.46 (s, 4.5H, rotamer 1), 1.33 (s, 5.5H, rotamer 2). ¹³C NMR (125MHz, CDCl₃, mixture of rotamers) δ 196.3, 196.1, 156.3, 155.9, 152.4,152.3, 140.0, 148.9, 137.0, 136.8, 127.6, 127.4, 121.8, 121.7, 79.7,79.6, 55.6, 55.3, 35.8, 35.6, 28.4, 28.2 ppm. IR (thin film) 2977, 1714,1688, 1588, 1224, 1170, 1142, 996 cm⁻¹.

tert-Butyl methyl(2-oxo-2-(pyridin-3-yl)ethyl)carbamate (2k)

Prepared according to general procedure B3 from 3-bromopyridine (3.26mL, 33.8 mmol), iPrMgCl (2.0 M in THF, 16.9 mL, 33.8 mmol), and 1a (3.93g, 16.9 mmol) to yield an off-yellow oil (1.86 g, 44%). R_(f)=0.26(EtOAc). ¹H NMR (500 MHz, CDCl₃, mixture of rotamers) δ 9.19-9.09 (m,1H, rotamers 1 & 2), 8.86-8.73 (m, 1H, rotamers 1 & 2), 8.23 (tt, J=7.9,2.0 Hz, 1H, rotamers 1 & 2), 7.44 (ddd, J=17.3, 8.0, 4.9 Hz, 1H,rotamers 1 & 2), 4.63 (d, J=41.4 Hz, 2H, rotamers 1 & 2), 2.97 (d,J=14.5 Hz, 3H, rotamers 1 & 2), 1.43 (d, J=55.2 Hz, 9H, rotamers 1 & 2).¹³C NMR (126 MHz, CDCl₃, mixture of rotamers) δ 194.4, 194.0, 153.9,149.3, 149.1, 135.3, 135.2, 123.9, 123.7, 85.8, 85.0, 55.8, 55.3, 28.3,28.3, 28.2. IR (thin film) 1684, 1390, 1234, 1146, 987, 879 cm⁻¹.

tert-Butyl (2-(6-methoxypyridin-2-yl)-2-oxoethyl)(methyl)carbamate (2l)

Prepared according to general procedure B3 from2-bromo-6-methoxypyridine (2.35 g, 12.5 mmol), iPrMgCl (2.0 M in THF,6.3 mL, 12.5 mmol), and 1a (3.0 g, 12.9 mmol) to yield an off-yellow oil(625 mg, 18%). R_(f)=0.38 (6:4 hexanes/EtOAc). ¹H NMR (500 MHz, CDCl₃,mixture of rotamers) δ 7.74-7.64 (m, 2H, rotamers 1 &2), 6.99-6.95 (m,1H, rotamers 1 & 2), 4.93 (s, 1.1H, rotamer 1), 4.82 (s, 0.9H, rotamer2), 4.03-3.93 (m, 3H, rotamers 1 & 2), 2.98 (d, J=1.3 Hz, 3H, rotamers 1& 2), 1.51 (s, 4.6H, rotamer 1), 1.39 (m, 4.4H, rotamer 2) ppm. ¹³C NMR(125 MHz, CDCl₃, mixture of rotamers) δ 192.0, 191.8, 159.4, 159.3,152.4, 152.0, 145.8, 145.7, 135.3, 135.1, 111.9, 111.1, 111.1, 75.8,75.7, 51.7, 51.4, 49.6, 49.5, 31.8, 31.7, 24.4, 24.3 ppm. IR (thin film)1714, 1690, 1590, 1468, 1389, 1364, 1324, 1272, 1225, 1171, 1142, 1032cm⁻¹. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C₁₄H₂₀N₂O₄Na 303.1321; Found303.1341.

tert-Butyl (2-(3-methoxypyridin-2-yl)-2-oxoethyl)(methyl)carbamate (2m)

Prepared according to general procedure B3 from3-bromo-3-methoxypyridine (2 g, 10.62 mmol), iPrMgCl (2.0 M in THF, 5.84mL, 11.69 mmol), and 1a (2.54 g, 10.93 mmol) to yield an off-yellow oil(480 mg, 16%). R_(f)=0.43 (EtOAc). ¹H NMR (500 MHz, CDCl₃, mixture ofrotamers) δ 8.32-8.16 (m, 1.1H), 7.44-7.28 (m, 1.3H), 7.22-7.13 (m,0.6H), 4.71 (d, J=58.9 Hz, 1.3H), 4.09 (d, J=37.8 Hz, 0.7H), 3.93-3.79(m, 2.4H), 3.71-3.64 (m, 0.6H), 3.16 (d, J=5.7 Hz, 0.4H), 2.97-2.86 (m,2.6H), 1.62-1.30 (m, 9H). ¹³C NMR (125 MHz, CDCl₃, mixture of rotamers)δ 191.0, 190.9, 151.6, 151.2, 150.9, 150.8, 150.5, 137.3, 137.2, 135.6,135.6, 132.8, 123.2, 123.0, 119.0, 115.6, 115.2, 115.2, 75.0, 74.9,74.8, 56.5, 56.5, 52.7, 52.1, 51.0, 50.7, 45.4, 44.9, 31.1, 31.0, 30.9,23.6, 23.5.

tert-Butyl (2-(4-methoxypyridin-2-yl)-2-oxoethyl)(methyl)carbamate (2n)

Prepared according to general procedure B3 from2-bromo-4-methoxypyridine (2.5 g, 13.3 mmol), iPrMgCl (2.0 M in THF, 7.3mL, 14.6 mmol), and 1a (3.18 g, 13.7 mmol) to yield an off-white solid(1.64 g, 44%) after purification via flash chromatography (gradient:95:5 hexanes/EtOAc to 3:2 hexanes/EtOAc). R_(f)=0.38 (3:2hexanes/EtOAc). ¹H NMR (500 MHz, CDCl₃, mixture of rotamers) δ 8.48-8.40(m, 1H, rotamers 1 & 2), 7.58-7.51 (m, 1H, rotamers 1 & 2), 7.02-6.93(m, 1H, rotamers 1 & 2), 4.89 (s, 1H, rotamer 1), 4.83 (s, 1H, rotamer2), 3.90 (s, 1.5H, rotamer 2), 3.88 (s, 1.5H, rotamer 1), 2.95 (s, 3H,rotamers 1 & 2), 1.48 (s, 4.5H, rotamer 2), 1.36 (s, 4.5H, rotamer 1).¹³C NMR (125 MHz, CDCl₃, mixture of rotamers) δ 196.3, 196.0, 166.5,166.4, 156.3, 155.9, 154.3, 154.2, 150.2, 150.1, 114.2, 106.9, 79.7,79.6, 55.8, 55.5, 55.4, 35.8, 35.5, 28.4, 28.2.

tert-Butylmethyl(2-oxo-2-(6-(trifluoromethyl)pyridin-2-yl)ethyl)carbamate (2o)

Prepared according to general procedure B2 from2-bromo-6-trifluoromethylpyridine (2 g, 10.62 mmol), nBuLi (2.5M inhexanes, 5.7 mL, 14.2 mmol), and 1a (3.0 g, 12.9 mmol) to yield anoff-yellow oil (1.60 g, 39%). R_(f)=0.66 (3:2 hexanes/EtOAc). IR (thinfilm): 1721, 1690, 1390, 1366, 1338, 1226, 1140, 1112, 997 cm⁻¹. ¹H NMR(500 MHz, CDCl₃, mixture of rotamers) δ 8.23-8.18 (m, 1H, rotamer 1 &2), 8.09-8.01 (m, 1H, rotamer 1 & 2), 7.90-7.84 (m, 1H, rotamer 1 & 2),4.93 (s, 1.1H, rotamer 1), 4.85 (s, 0.9H, rotamer 2), 2.98 (s, 3H,rotamer 1 & 2), 1.47 (s, 5.4H, rotamer 1), 1.36 (s, 3.6H, rotamer 2)ppm. ¹³C NMR (125 MHz, CDCl₃, mixture of rotamers) δ 191.4, 191.3,152.3, 151.8, 148.3 (2), 143.9, 143.8, 143.6, 143.5, 134.9, 134.7,120.3, 120.2, 120.1, 120.1, 120.0 (2), 118.2, 116.0, 113.8, 76.0, 75.9,51.6, 51.5, 31.9, 31.7, 24.4, 24.2 ppm. IR (thin film): 1721, 1690,1390, 1366, 1338, 1226, 1140, 1112, 997 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+Calcd for C₁₄H₁₇N₂O₃F₃Na 341.1089; Found 341.1104.

tert-Butyl (2-(6-fluoropyridin-2-yl)-2-oxoethyl)(methyl)carbamate (2p)

Prepared according to general procedure B3 from 3-bromo-6-fluoropyridine(2 g, 11.36 mmol), iPrMgCl (2.0 M in THF, 6.25 mL, 12.50 mmol), and 1a(2.64 g, 11.36 mmol) to yield an off-yellow oil (780 mg, 26%).R_(f)=0.46 (3:2 hexanes/EtOAc). ¹H NMR (500 MHz, CDCl₃, mixture ofrotamers) δ 8.05-7.87 (m, 2H, rotamer 1 &2), 7.24-7.08 (m, 1H, rotamer 1& 2), 4.83 (s, 1H, rotamer 1), 4.77 (s, 1H, rotamer 2), 2.96 (d, J=2.2Hz, 3H, rotamers 1 & 2), 1.48 (s, 5H, rotamer 1), 1.36 (s, 5H, rotamer2) ppm. ¹³C NMR (125 MHz, CDCl₃, mixture of rotamers) δ 192.4, 192.2,160.8, 160.8, 158.9, 158.8, 153.7, 153.2, 147.9, 147.8, 147.7, 139.6,139.6, 139.5, 139.4, 116.8, 116.8, 116.8, 116.7, 112.9, 111.9, 111.7,111.6, 77.3 (2), 53.1, 52.8, 33.3, 33.0, 25.8, 25.6 ppm. IR (thin film):1718, 1691, 1577, 1449, 1389, 1365, 1267, 1225, 1172, 1146, 1017, 994cm⁻¹.

tert-Butyl ethyl(2-oxo-2-(pyridin-2-yl)ethyl)carbamate (2q)

Prepared according to general procedure B3 from 2-bromopyridine (1.3 mL,13.6 mmol), iPrMgCl (2.0 M in THF, 7.5 mL, 15 mmol), and 1d (3.45 g,14.0 mmol) to yield an off-yellow oil (2.59 g, 72%). R_(f)=0.48 (1:1hexanes/EtOAc). ¹H NMR (500 MHz, CDCl₃, mixture of rotamers) δ 8.63 (dd,J=12.1, 4.9 Hz, 1H, rotamer 1 & 2), 8.01 (t, J=8.6 Hz, 1H, rotamer 1 &2), 7.83 (dt, J=19.6, 7.4 Hz, 1H, rotamer 1 & 2), 7.47 (ddd, J=18.4,7.5, 4.9 Hz, 1H, rotamer 1 & 2), 4.90 (s, 1H, rotamer 1), 4.82 (s, 1H,rotamer 2), 3.38 (q, J=7.2 Hz, 1H, rotamer 1), 3.32 (q, J=7.2 Hz, 1H,rotamer 2), 1.47 (s, 4.5H, rotamer 1), 1.33 (s, 4.5H, rotamer 2), 1.11(t, J=7.3 Hz, 3H, rotamer 1 & 2) ppm. ¹³C NMR (125 MHz, CDCl₃, mixtureof rotamers) δ 192.4, 192.3, 151.9, 151.4, 148.5, 148.5, 145.0, 144.9,133.1, 133.0, 132.9, 123.6, 123.5, 123.4, 117.9, 117.8, 75.7, 75.6,49.3, 49.3, 39.5, 38.9, 24.5, 24.3, 9.8, 9.4 ppm. IR (thin film): 1715,1686, 1421, 1391, 1365, 1282, 1251, 1224, 1167, 1142, 996 cm⁻¹. HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for C₁₄H₂₀N₂O₃Na 287.1372; Found 287.1393.

tert-Butyl methyl(2-(6-methylpyridin-2-yl)-2-oxoethyl)carbamate (2r)

Prepared according to general procedure B2 from6-methyl-2-bromopyrididne (2.00 g, 11.62 mmol), n-BuLi (2.5 M inhexanes, 10.22 mL, 25.56 mmol), and 1a (2.70 g, 11.62 mmol) as a yellowoil (690 mg, 22%). R_(f)=0.42 (7:3 hexanes/EtOAc). ¹H NMR (500 MHz,CDCl₃, mixture of rotamers) δ 7.84-7.80 (m, 1H, rotamers 1 & 2),7.73-7.67 (m, 1H, rotamers 1 & 2), 7.34-7.30 (m, 1H, rotamers 1 & 2),4.93 (s, 1H, rotamer 1), 4.84 (s, 1H, rotamer 2), 2.97 (s, 1.5H, rotamer1), 2.96 (s, 1.5H, rotamer 2), 2.60 (s, 1.5H, rotamer 1), 2.57 (s, 1.5H,rotamer 2), 1.49 (s, 4.5H, rotamer 1), 1.37 (s, 4.5H, rotamer 2). ¹³CNMR (125 MHz, CDCl₃, mixture of rotamers) δ 196.7, 196.4, 158.0, 156.0,152.0, 134.0, 136.8, 127.1, 127.0, 118.8, 118.8, 79.7, 79.6, 55.7, 55.3,35.8, 35.6, 28.4, 28.2, 24.3, 22.3, 13.8. IR (thin film): 1712, 1690,1591, 1479, 1451, 1388, 1365, 1292, 1221, 1171, 1021, 933 cm⁻¹.

tert-Butyl (2-(6-(tert-butyl)pyridin-2-yl)-2-oxoethyl) (methyl)carbamate(2s)

Prepared according to general procedure B2 from6-tert-butyl-2-bromopyridine (1.80 g, 8.40 mmol), n-BuLi (2.5 M inhexanes, 7.4 mL, 18.48 mmol), and 1a (1.95 g, 8.40 mmol) as a yellow oil(390 mg, 15%). R_(f)=0.50 (4:1 hexanes/EtOAc). ¹H NMR (500 MHz, CDCl₃,mixture of rotamers) δ 7.82-7.73 (m, 2H, rotamers 1 & 2), 7.54-7.49 (m,1H, rotamers 1 & 2), 4.97 (s, 1.05H, rotamer 1), 4.87 (s, 0.95H, rotamer2), 2.97 (d, J=8.9 Hz, 3H, rotamers 1 & 2), 1.49 (s, 5H, rotamer 1),1.43-1.34 (m, 14H, rotamers 1 & 2). ¹³C NMR (125 MHz, CDCl₃, mixture ofrotamers) δ 196.8, 168.9, 168.8, 156.4, 156.0, 151.2, 151.1, 137.1,137.0, 123.1, 123.0, 118.5, 79.7, 79.5, 55.5, 55.5, 37.6, 35.7, 35.7,30.2, 30.1, 28.4, 28.2. IR (thin film): 1714, 1692, 1586, 1480, 1451,1388, 1364, 1293, 1224, 1170, 1141, 1005, 993 cm⁻¹.

Example 5: General Procedure C (Synthesis of Deprotected α-Aminoketones)

2-(Methylamino)-1-phenylethan-1-one .HCl (3a)

To a stirring solution of anhydrous MeOH (35 mL) in a 100 mL Erlenmeyerflask was added acetyl chloride (3.5 mL, 50.16 mmol) dropwise. After 10minutes, the resulting methanolic hydrogen chloride solution was addedto a 50 mL round bottom flask containing 2a (2.43 g, 10.03 mmol). After1 h, the solvent was removed under reduced pressure yielding a finewhite powder (1.69 g, 91%), which was used without further purification.¹H NMR (CD₃OD, 500 MHz): δ 8.07-8.04 (m, 1H), 7.73 (t, J=7.5 Hz, 1H),7.59 (t, J=7.5 Hz, 2H), 4.79 (s, 2H), 2.85 (s, 3H). ¹³C NMR (CD₃OD, 125MHz): δ 191.5, 134.5, 133.5, 128.8, 127.9, 54.0, 32.2 ppm. IR (thinfilm) 2945, 2911, 2808, 2756, 2434, 1690, 1597, 1574, 1472, 1449, 1424,1373, 1242, 1013, 940, 884, 764 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcdfor C₉H₁₂NO 150.0919; Found 150.0919.

1-(4-Methoxyphenyl)-2-(methylamino)ethan-1-one .HCl (3b)

Prepared according to general procedure C with 2b (2.23 g, 8.0 mmol) asa white powder (1.59 g, 92%). ¹H NMR (CD₃OD, 500 MHz): δ 8.02 (t, J=8.5Hz, 2H), 7.09 (t, J=8.5 Hz, 2H), 4.70 (s, 2H), 3.91 (s, 3H), 2.83 (s,3H). ¹³C NMR (CD₃OD, 125 MHz): δ 189.7, 165.1, 130.4, 126.4, 114.0,54.9, 53.6, 32.2 ppm. IR (thin film) 2936, 2742, 2689, 1679, 1599, 1573,1423, 1362, 1252, 1183, 1027, 1013, 944, 831 cm⁻¹.

1-(4-Methoxyphenyl)-2-(methylamino)-3-phenylpropan-1-one .HCl (3c)

Prepared according to general procedure C with 2c (3.37 g, 9.12 g) as awhite powder (2.48 g, 89%). ¹H NMR (CD₃OD, 500 MHz): δ 7.93 (d, J=8.5Hz, 2H), 7.27-7.21 (m, 3H), 7.16-7.12 (m, 2H), 6.99 (d, J=8.5 Hz, 2H),5.41 (t, J=6.5 Hz, 1H), 3.88 (s, 3H), 3.77-3.27 (m, 2H), 2.71 (s, 3H).¹³C NMR (CD₃OD, 125 MHz): δ 193.1, 165.1, 133.3, 131.3, 129.4, 128.6,127.5, 127.0, 114.0, 63.3, 54.9, 36.9, 31.4 ppm. IR 2931, 2658, 2604,1673, 1601, 1578, 1512, 1465, 1417, 1353, 1254, 1242, 1175, 1148, 1030,1014, 939, 842, 767 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₁₇H₂₀NO₂270.1494; Found 270.1497.

3-Methyl-2-(methylamino)-1-phenylbutan-1-one .HCl (3d)

Prepared according to general procedure C with 2d (1.25 g, 4.29 mmol) asa white powder (890 mg, 91%). ¹H NMR (CD₃OD, 500 MHz): δ 8.08 (d, J=8.5Hz, 2H), 7.76 (t, J=7.5 Hz, 1H), 7.62 (t, J=7.5 Hz, 2H), 5.20 (d, J=3Hz, 1H), 2.74 (s, 3H), 2.45-2.35 (m, 1H), 1.16 (d, J=7 Hz, 3H), 0.92 (d,J=7 Hz, 3H). ¹³C NMR (CD₃OD, 125 MHz): δ 195.1, 134.9, 134.8, 129.0,128.7, 68.1, 68.1, 32.2, 30.0, 17.3, 16.4 ppm. IR (thin film) 2970,2686, 2471, 1677, 1594, 1471, 1449, 1357, 1264, 1234, 1005, 980, 941,896, 832, 762 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₁₂H₁₈NO192.1388; Found 192.1389.

2-(Ethylamino)-1-(4-methoxyphenyl)ethan-1-one .HCl (3e)

Prepared according to general procedure C with 2e (63.90 mg, 0.21 mmol)as a pink powder (34.4 mg, 70%). ¹H NMR (CD₃OD, 500 MHz): δ 7.78 (d,J=9.0 Hz, 2H), 6.78 (d, J=9.0 Hz, 2H), 3.93 (s, 2H), 3.70 (s, 3H), 2.57(q, J=7.0 Hz, 2H), 2.26 (brs, 1H), 1.03 (t, J=7.0 Hz, 3H). ¹³C NMR(CD₃OD, 125 MHz): δ 196.2, 163.5, 129.8, 128.5, 113.7, 55.3, 55.0, 44.0,15.2 ppm. IR (neat): 2986, 2928, 2892, 2839, 2779, 2750, 2716, 2678,1675, 1600, 1573, 1513, 1449, 1430, 1396, 1327, 1314, 1244, 1180, 1125,1038, 1021, 977, 907, 835, 813, 802, 612, 584 cm⁻¹.

2-(Ethylamino)-1-phenylethan-1-one .HCl (3f)

Prepared according to general procedure C with 2f (0.28 g, 1.07 mmol) asa white powder (0.15 g, 70%). ¹H NMR (CD₃OD, 500 MHz): δ 8.04 (dd,J=8.5, 1.5 Hz, 2H), 7.72 (tt, J=7.5, 1.0 Hz, 1H), 7.58 (t, J=8.0 Hz,2H), 4.76 (s, 2H), 3.20 (q, J=7.5 Hz, 2H), 1.39 (t, J=7.5 Hz, 3H). ¹³CNMR (CD₃OD, 75 MHz): δ 191.8, 134.8, 133.8, 129.0, 128.1, 52.3, 42.8,10.3 ppm.

(4-Methoxyphenyl)(pyrrolidin-2-yl)methanone .HCl (3 g)

Prepared according to general procedure C with 2 g (750 mg, 2.45 mmol)as a white powder (356 mg, 60%). ¹H NMR (500 MHz, CD₃OD) δ 8.07 (d,J=9.1 Hz, 2H), 7.11 (d, J=9.1 Hz, 2H), 5.34 (dd, J=9.2, 7.1 Hz, 1H),3.92 (s, 2H), 3.45 (td, J=7.0, 1.8 Hz, 2H), 2.70 (tdd, J=7.4, 4.7, 1.8Hz, 1H), 2.28-2.06 (m, 1H), 2.07-1.85 (m, 2H) ppm. ¹³C NMR (125 MHz,CD₃OD) δ 191.9, 165.2, 131.3, 125.3, 114.1, 62.8, 54.9, 54.9, 46.0,29.8, 23.8 ppm. IR (thin film) 2843, 2631, 1668, 1597, 1574, 1422, 1243,1176, 997, 844 cm⁻¹. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C₁₂H₁₅NO₂Na228.1000; Found 228.1005.

1-(Benzo[d][1,3]dioxol-5-yl)-2-(methylamino)ethan-1-one .HCl (3h)

Prepared according to general procedure C with 2h (1.21 g, 4.13 mmol) asa white powder (755 mg, 80%). ¹H NMR (500 MHz, CD₃OD) δ 7.67 (dd, J=8.2,1.7 Hz, 1H), 7.47 (d, J=1.7 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.11 (s,2H), 4.66 (s, 2H), 2.82 (s, 3H) ppm. ¹³C NMR (125 MHz, CD₃OD) δ 189.4,153.4, 148.7, 128.1, 125.0, 108.0, 106.9, 102.5, 53.7, 32.2 ppm. IR(thin film) 2930, 2767, 2696, 2411, 1669, 1443, 1358, 1254, 1110, 1036,925, 827, 781 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₁₀H₁₂NO₃194.0817; Found 194.0825.

2-(Methylamino)-1-(o-tolyl)ethan-1-one .HCl (3i)

Prepared according to general procedure C with 2i (759 mg, 2.90 mmol) asa white powder (402 mg, 69%). ¹H NMR (500 MHz, CD₃OD) δ 7.89 (dd, J=7.8,1.3 Hz, 1H), 7.57-7.46 (m, 1H), 7.44-7.34 (m, 2H), 4.69 (s, 2H), 2.84(s, 3H), 2.59 (s, 3H) ppm. ¹³C NMR (125 MHz, CD₃OD) δ 193.7, 139.9,133.2, 132.7, 132.2, 129.4, 126.0, 55.2, 32.1, 20.5 ppm. IR (thin film)2922, 2689, 1684, 1570, 1455, 13346, 1233, 1002, 940, 756 cm⁻¹. HRMS(ESI-TOF) m/z: [M+H]+ Calcd for C₁₀H₁₄NO 164.1075; Found 164.1078.

2-(Methylamino)-1-(pyridin-2-yl)ethan-1-one .2HCl (3j)

Prepared according to general procedure C with 2j (4.93 g, 19.7 mmol) asa white powder (3.97 g, 90%). ¹H NMR (500 MHz, CD₃OD) δ 8.96 (d, J=5.8Hz, 1H), 8.89-8.70 (m, 1H), 8.27-8.17 (m, 2H), 4.91 (s, 2H), 2.78 (s,3H) ppm. IR (thin film) 3010, 1734, 1673, 1718, 1614, 1603, 1525, 1453,1375, 1253, 1221, 1164, 1025, 943, 855, 759 cm⁻¹. HRMS (ESI-TOF) m/z:[M+H]+ Calcd for C₈H₁₀N₂O 151.0871; Found 151.0871.

2-(Methylamino)-1-(pyridin-3-yl)ethan-1-one .2HCl (3k)

Prepared according to general procedure C with 2k (1.7 g, 6.8 mmol) as awhite powder (880 mg, 58%). ¹H NMR (500 MHz, DMSO-d₆) δ 9.31 (d, J=2.0Hz, 1H), 9.02 (dd, J=5.2, 1.7 Hz, 1H), 8.66 (dt, J=8.1, 1.9 Hz, 1H),7.97-7.90 (m, 1H), 4.86 (t, J=5.5 Hz, 2H), 2.61 (t, J=5.2 Hz, 3H). ¹³CNMR (125 MHz, DMSO-d₆) δ 191.3, 150.8, 146.4, 140.2, 131.1, 126.3, 54.2,33.2. IR (thin film) 2684, 2538, 2442, 1705, 1628, 1454, 1380, 1243,1128, 944, 786 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₈H₁N₂O151.0871; Found 151.0870.

1-(6-Methoxypyridin-2-yl)-2-(methylamino)ethan-1-one .2HCl (31)

Prepared according to general procedure C with 21 (550 mg, 1.96 mmol) asa white powder (208 mg, 42%). ¹H NMR (500 MHz, CD₃OD) δ 7.95-7.84 (m,1H), 7.74 (d, J=7.7 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 4.04 (s, 2H), 2.87(s, 3H) ppm. ¹³C NMR (125 MHz, CD₃OD) δ 192.2, 163.8, 148.0, 139.7,116.9, 115.1, 54.1, 52.9, 32.2 ppm. IR (thin film) 2929, 2747, 2687,2444, 1705, 1592, 1470, 1419, 1367, 1335, 1278, 1236, 1152, 1043, 1019,948, 909, 813 cm⁻¹.

1-(3-Methoxypyridin-2-yl)-2-(methylamino)ethan-1-one .2HCl (3m)

Prepared according to general procedure C with 2m (400 mg, 1.43 mmol) asa white powder (331 mg, 91%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.30 (dd,J=4.4, 1.2 Hz, 1H), 7.83-7.72 (m, 2H), 4.61 (t, J=5.9 Hz, 2H), 3.91 (s,3H), 2.60 (t, J=5.4 Hz, 3H). ¹³C NMR (125 MHz, DMSO-d₆) δ 191.4, 156.6,140.8, 138.8, 130.6, 122.8, 56.6, 55.3, 32.6.

1-(4-Methoxypyridin-2-yl)-2-(methylamino)ethan-1-one .2HCl (3n)

Prepared according to general procedure C with 2n (1.8 g, 6.42 mmol) asa white powder (1.52 g, 94%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.59 (d, J=5.6Hz, 1H), 7.56 (d, J=2.5 Hz, 1H), 7.35 (dd, J=5.7, 2.6 Hz, 1H), 4.74 (t,J=5.8 Hz, 2H), 3.94 (s, 3H), 2.64 (t, J=5.3 Hz, 3H). ¹³C NMR (125 MHz,DMSO-d₆) δ 198.07, 171.75, 157.13, 156.06, 155.98, 120.04, 112.92,61.28, 58.96, 37.82.

2-(Methylamino)-1-(6-(trifluoromethyl)pyridin-2-yl)ethan-1-one HCl (3o)

Prepared according to general procedure C with 2o (1.50 g, 4.71 mmol) asa white powder (490 mg, 36%). ¹H NMR (500 MHz, Methanol-d₄) δ 8.40-8.30(m, 2H), 8.17 (dt, J=7.1, 1.3 Hz, 1H), 4.91 (s, 2H), 2.89 (s, 3H). ¹³CNMR (125 MHz, Methanol-d₄) δ 191.5, 150.7, 147.4 (q, J=35.3 Hz), 140.1,125.2 (q, J=2.8 Hz), 124.4, 121.1 (q, J=273.4 Hz), 53.8, 32.3 ppm. IR(thin film): 3007, 2703, 2602, 1718, 1601, 1528, 1457, 1372, 1338, 1297,1252, 1231, 1167, 1037, 777 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd forC₉H₁₀N₂OF₃ 219.0745; Found 219.0773.

1-(6-Fluoropyridin-2-yl)-2-(methylamino)ethan-1-one .HCl (3p)

Prepared according to general procedure C with 2p (700 mg, 2.61 mmol) asa white powder (450 mg, 84%). ¹H NMR (500 MHz, Methanol-d₄) δ 8.26-8.16(m, 1H), 8.07 (ddq, J=7.3, 1.9, 0.9 Hz, 1H), 7.45 (ddq, J=8.3, 2.7, 0.9Hz, 1H), 4.87 (s, 2H), 2.85 (s, 3H) ppm. ¹³C NMR (125 MHz, Methanol-d₄)δ 192.5, 164.1 (d, J=243.2 Hz), 149.9, 144.5 (d, J=7.8 Hz), 141.0, 120.8(d, J=3.8 Hz), 117.4 (d, J=230.8 Hz), 116.8 (d, J=36.5 Hz), 55.20,33.61. IR (thin film): 3007, 2702, 2603, 1718, 1602, 1528, 1456, 1371,1298, 1253, 1233, 1167, 1052, 1036, 777 cm⁻¹.

2-(Ethylamino)-1-(pyridin-2-yl)ethan-1-one .2HCl (3q)

Prepared according to general procedure C with 2q (2.40 g, 9.08 mmol) asa white powder (1.85 g, 86%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.75 (d, J=4.2Hz, 1H), 8.05 (dd, J=23.8, 7.5 Hz, 2H), 7.76 (t, J=5.7 Hz, 1H), 4.72 (t,J=5.7 Hz, 2H), 3.03 (q, J=6.4 Hz, 2H), 1.25 (t, J=7.0 Hz, 3H). ¹³C NMR(125 MHz, DMSO-d₆) δ 198.2, 155.5, 154.7 (d, J=22.4 Hz), 143.4, 134.3,127.0, 56.8, 47.2, 16.2. IR (thin film): 3007, 2606, 1718, 1602, 1528,1457, 1442, 1390, 1372, 1356, 1333, 1257, 1251, 1231, 1220, 1167, 1052,1037, 776 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₉H₁₃N₂O 165.1028;Found 165.1031.

2-(Methylamino)-1-(6-methylpyridin-2-yl)ethan-1-one .2HCl (3r)

Prepared according to general procedure C with 2r (690 mg, 2.61 mmol) asa brown solid (504 mg, 81%). ¹H NMR (500 MHz, DMSO-d₆) δ 7.96 (t, J=7.6Hz, 1H), 7.85 (d, J=7.4 Hz, 1H), 7.63 (d, J=7.5 Hz, 1H), 4.70 (s, 2H),2.65-2.59 (m, 3H), 2.56 (s, 3H). ¹³C NMR (125 MHz, DMSO-d₆) δ 193.5,158.7, 150.4, 138.6, 129.1, 119.6, 53.9, 33.1, 24.3.

1-(6-(tert-Butyl)pyridin-2-yl)-2-(methylamino)ethan-1-one .2HCl (3s)

Prepared according to general procedure C with 2s (390 mg, 1.27 mmol) asa brown solid (308 mg, 87%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.00 (s, 1H),7.83 (dd, J=18.4, 5.8 Hz, 2H), 4.74 (s, 2H), 2.64 (s, 3H), 1.36 (s, 9H).¹³C NMR (125 MHz, DMSO-d₆) δ 197.8, 162.4, 154.5, 130.4, 127.6, 113.3,55.3, 30.7, 27.9, 14.3.

Example 6: General Procedure D (Synthesis of Cyanobenzamides)

N-Cyano-2-fluorobenzamide (4a)

A one-necked 500 mL round bottom flask open to the atmosphere, equippedwith a magnetic stirring bar is charged with cyanamide (6.3 g, 0.15 mol)and distilled water (200 mL). Sodium hydroxide pellets (12.3 g, 0.308mol) are then added in portions (˜3×4 g) over a 15 minute period. Themixture is then stirred for 30 min. at room temperature and then cooledto 0° C. The flask is fitted with a 1000 mL addition funnel and theaddition funnel charged with 2-fluorobenzoyl chloride (23.5 g, 0.15mol). The 2-fluorobenzoyl chloride is then added dropwise over a span of20 min. After addition of the benzoyl chloride the reaction is stirredfor an additional 3 hours at room temperature. The mixture istransferred to a 500 mL separatory funnel and washed with diethyl ether(1×50 mL). The aqueous layer is then transferred to a 1-L Erlenmeyerflask equipped with a magnetic stirring bar and acidified to pH=2 withconc. HCl (approx. 15 mL). Dichloromethane (200 mL) is then added todissolve the solids and the mixture transferred to a 500 mL separatoryfunnel. After separation of the layers, the aqueous fraction isextracted with dichlormethane (2×100 mL) and the combined organics driedover anhydrous Na₂SO₄. The organics were filtered through a sinteredglass funnel and the resultant sodium sulfate was washed withdichloromethane (2×50 mL). The solvent was removed on a rotaryevaporator and then the flask transferred to a high-vac line for 3hours. The resulting white solid (18.7 g, 76%) was then used withoutfurther purification. R_(f)=0.16 (100% EtOAc). ¹H NMR (500 MHz, DMSO-d₆)δ 7.74 (td, J=7.5, 1.8 Hz, 1H), 7.71-7.63 (m, 1H), 7.41-7.32 (m, 2H).¹³C NMR (125 MHz, DMSO-d₆) δ 164.9, 159.9 (d, J=253.7 Hz), 135.6 (d,J=8.9 Hz), 130.9 (d, J=1.7 Hz), 125.3 (d, J=3.6 Hz), 120.3 (d, J=12.6Hz), 117.1 (d, J=21.4 Hz), 108.7. IR (thin film) 3269, 2260, 1701, 1610,1435, 1279, 1220, 890, 787 cm⁻¹.

N-Cyano-4-methoxybenzamide (4b)

Prepared according to general procedure D with 4-methoxybenzoyl chloride(10.03 g, 59.5 mmol) and cyanamide as a white solid (9.09 g, 87%).R_(f)=0.10 (100% EtOAc). ¹H NMR (500 MHz, DMSO-d₆) δ 7.98-7.83 (m, 2H),7.05-6.79 (m, 2H), 3.81 (s, 3H). ¹³C NMR (125 MHz, DMSO-d₆) δ 172.2,168.0, 136.5, 128.2, 119.0, 114.4, 60.6. IR (thin film) 3233, 2256,1670, 1601, 1450, 1257, 1180, 1022, 840, 755 cm⁻¹.

4-Chloro-N-cyanobenzamide (4c)

Prepared according to general procedure D with 4-chlorobenzoyl chloride(10.52 g, 57.5 mmol) and cyanamide as a white solid (9.24 g, 86%).R_(f)=0.13 (100% EtOAc). ¹H NMR (500 MHz, CD₃OD) δ 7.88 (d, J=8.6 Hz,2H), 7.55 (d, J=8.6 Hz, 2H). ¹³C NMR (125 MHz, CD₃OD) δ 166.5, 139.8,129.5, 129.1, 128.9, 108.1 ppm. IR (thin film) 3220, 2260, 1672, 1592,1447, 1098, 1010, 841, 747 cm⁻¹.

N-Cyanobenzamide (4d)

Prepared according to general procedure D with benzoyl chloride (8.36 g,59.5 mmol) and cyanamide as a white solid (6.41 g, 74%). R_(f)=0.16(100% EtOAc). ¹H NMR (500 MHz, CD₃OD) δ 7.90 (d, J=7.9 Hz, 1H),7.75-7.63 (m, 1H), 7.54 (d, J=1.6 Hz, 1H) ppm. ¹³C NMR (125 MHz, CD₃OD)δ 167.5, 133.5, 130.5, 128.6, 127.9, 108.3 ppm. IR (thin film) 3234,2254, 1673, 1601, 1502, 1460, 1265, 1001, 795 cm⁻¹.

N-Cyano-4-fluorobenzamide (4e)

Prepared according to general procedure D with 4-fluorobenzoylchloride(13.4 g, 84.5 mmol) and cyanamide as a white solid (9.85 g,71%). R_(f)=0.18 (EtOAc). ¹H NMR (500 MHz, CD₃OD) δ 8.05-7.86 (m, 2H),7.28 (t, J=8.7 Hz, 2H) ppm. ¹³C NMR (125 MHz, CD₃OD) δ 167.1, 165.6 (d,J_(CF)=143.9 Hz), 130.8 (d, J_(CF)=9.5 Hz), 126.8 (d, J_(CF)=3.2 Hz),115.7 (d, J_(CF)=22.5 Hz), 108.0 ppm. IR (thin film) 3252, 2254, 1678,1593, 1455, 1236, 1166, 851, 753 cm⁻¹.

2,4-Dichloro-N-cyanobenzamide (4f)

Prepared according to general procedure D with 2-4-dicholorobenzoylchloride (11.8 g, 84.5 mmol) and cyanamide as a white solid (12.17 g,67%). ¹H NMR (500 MHz, CD₃OD) δ 7.65 (s, 1H), 7.60 (d, J=8.3 Hz, 1H),7.49 (d, J=8.3 Hz, 1H) ppm. ¹³C NMR (125 MHz, CD₃OD) δ 166.2, 137.9,132.2, 130.9, 130.3, 130.0, 127.4, 107.0 ppm. IR (thin film) 3129, 2280,1693, 1449, 1372, 1289, 1240, 1111, 904, 829, 803, 760 cm⁻¹.

3-Chloro-N-cyanobenzamide (4 g)

Prepared according to general procedure D with 3-chlorobenzoyl chloride(10.9 g, 62.4 mmol) and cyanamide as a white solid (9.2 g, 81%). ¹H NMR(500 MHz, CD₃OD) δ 7.89 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.67 (dd,J=1.5, 8.0 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H). ¹³C NMR (125 MHz, CD₃OD) δ165.9, 134.7, 133.3, 132.3, 130.3, 127.9, 126.2, 107.6 ppm.

2-Chloro-N-cyanobenzamide (4h)

Prepared according to general procedure D with 2-chlorobenzoyl chloride(11.0 g, 63.0 mmol) and cyanamide as a white solid (10.2 g, 89%). ¹H NMR(500 MHz, CD₃OD) δ 7.57 (d, J=7.5 Hz, 1H), 7.54 (d, J=3.5 Hz, 2H), 7.44(sep, J=4.0 Hz, 1H). ¹³C NMR (125 MHz, CD₃OD) δ 167.12, 132.58, 132.29,130.93, 130.14, 128.95, 127.00, 107.14 ppm.

N-Cyano-3-fluorobenzamide (4i)

Prepared according to general procedure D with 3-fluorobenzoyl chlorideand cyanamide as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 7.77-7.71(m, 1H), 7.70-7.65 (m, 1H), 7.60 (td, J=8.0, 5.7 Hz, 1H), 7.53 (td,J=8.5, 2.6 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆) δ 166.5 (d, J=2.7 Hz),162.3 (d, J=245.5 Hz), 133.1 (d, J=7.3 Hz), 131.6 (d, J=8.1 Hz), 124.9(d, J=2.9 Hz), 121.0 (d, J=21.0 Hz), 115.5 (d, J=23.6 Hz), 109.4. IR(thin film) 3151, 1703, 1588, 1460, 1285, 1262, 1181, 920, 902 cm⁻¹.

4-Bromo-N-cyanobenzamide (4j)

Prepared according to general procedure D with 4-bromobenzoyl chloride(12 g, 55 mmol) and cyanamide (4.6 g, 109 mmol) as a white solid (4.62g, 37%). R_(f)=0.11 (100% EtOAc). ¹H NMR (500 MHz, DMSO-d₆) δ 8.65-8.60(m, 2H), 8.57 (dd, J=8.6, 2.8 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ166.7, 132.4, 130.7, 129.8, 128.3, 109.2. IR (thin film) 3221, 2260,2672, 1586, 1445, 1267, 1075, 838, 742 cm⁻¹.

Example 7: General Procedure E (Synthesis of4-Aryl-2-N-acyl-2-aminoimidzoles)

2-Fluoro-N-(1-methyl-4-phenyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5a)

To a flame dried 50 mL round-bottom flask equipped with a magnetic stirbar under and N₂ atmosphere was added 4a (146 mg, 0.89 mmol) and iPr₂NEt(0.42 mL, 2.42 mmol). Chlorotrimethylsilane (0.12 mL, 0.93 mmol) wasthen added, and the reaction was allowed to proceed at room temperaturefor 15 minutes. 3a (150 mg, 0.81 mmol) was then added in a singleportion, and the reaction was allowed to proceed for 1.5 h. SaturatedNaHCO₃(10 mL) was added to quench the reaction, the reaction waspartitioned and extracted with CH₂Cl₂ (15 mL). The organics were driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresulting crude material was then taken up in CH₂Cl₂ (10 mL) andtransferred to a 25 mL round-bottom flask equipped with a magnetic stirbard under a N₂ atmosphere. Trifluoroacetic acid (0.1 mL) was then addedto the flask, and the reaction was monitored by thin layerchromatography. After 4 hours, the reaction was quenched upon theaddition of saturated NaHCO₃(15 mL), and the suspension was extractedwith CH₂Cl₂ (2×15 mL). The combined organics were collected and driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresulting crude material was then purified by column chromatography,eluting 6:4 hexanes/EtOAc to yield a white solid (213.3 mg, 89%).R_(f)=0.16 (6:4 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.09 (dt,J=7.5 Hz, 1.5 Hz, 1H), 7.52 (d, J=8 Hz, 2H), 7.47-7.35 (m, 1H), 7.36 (t,J=7 Hz, 2H), 7.26 (t, J=7 Hz, 1H), 7.19 (t, J=8 Hz, 1H), 7.11 (dd, J=8.5Hz, 3.5 Hz, 1H), 6.90 (s, 1H), 3.59 (s, 3H). ¹³C NMR (125 MHz, CDCl₃,) δ169.4, 161.3 (d, J_(CF)=252.8 Hz), 146.1, 132.8 (d, J_(CF)=9.0 Hz),131.8 (d, J_(CF)=1.8 Hz), 130.1, 128.9, 127.7, 124.2, 124.1 (d,J_(CF)=3.6 Hz), 116.5 (d, J_(CF)=23.5 Hz), 112.8, 32.3 ppm. IR (thinfilm) 1168, 1619, 1561, 1540, 1481, 1463, 1362, 1287, 1218, 903, 723cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₁₇H₁₅N₃OF 296.1199; Found296.1205.

4-Methoxy-N-(1-methyl-4-phenyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5b)

Prepared according to general procedure E from 4b (157 mg, 0.89 mmol),iPr₂NEt (0.42 mL, 2.42 mmol), chlorotrimethylsilane (0.12 mL, 0.93mmol), and 3a (150 mg, 0.81 mmol) to yield a white solid (191.4, 77%).R_(f)=0.19 (6:4 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.19 (d,J=8.5 Hz, 2H), 7.47 (d, J=8 Hz, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.23 (t,J=7.5 Hz, 1H), 6.87 (d, J=8.5 Hz, 2H), 6.80 (s, 1H), 3.78 (s, 3H), 3.54(s, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 171.8, 162.1, 147.5, 130.3, 129.9,129.4, 128.9, 128.8, 127.5, 124.0, 113.2, 112.4, 55.3, 32.1 ppm. IR(thin film) 2937, 2828, 1670, 1605, 1563, 1516, 1456, 1400, 1355, 1282,1250, 1175, 1162, 1101, 1083, 1028, 956, 906, 846, 779 cm⁻¹.

4-Chloro-N-(1-methyl-4-phenyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5c)

Prepared according to general procedure E from 4c (161 mg, 0.89 mmol),iPr₂NEt (0.42 mL, 2.42 mmol), chlorotrimethylsilane (0.12 mL, 0.93mmol), and 3a (150 mg, 0.81 mmol) to yield a white solid (205 mg, 81%).R_(f)=0.19 (6:4 hexanes/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ 8.28 (d, J=6.8Hz, 1H), 7.51-7.34 (m, 7H), 7.31-7.27 (m, 1H), 6.80 (s, 1H), 3.61 (s,3H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 173.7, 149.6, 137.3, 131.1, 129.0,128.9, 128.7, 128.0, 128.0, 124.1, 124.1, 111.5, 31.9 ppm. IR (thinfilm) 1684, 1614, 1561, 1462, 1403, 1358, 1286, 1261, 1217, 906, 753,724 cm 1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₁₇H₁₅N₃OC₁ 312.0904;Found 312.0916.

N-(1-Methyl-4-phenyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide (5d)

Prepared according to general procedure E from 4d (130 mg, 0.89 mmol),iPr₂NEt (0.42 mL, 2.42 mmol), chlorotrimethylsilane (0.12 mL, 0.93mmol), and 3a (150 mg, 0.81 mmol) to yield a white solid (173.8 mg,77%). R_(f)=0.31 (6:4 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.28(dd, J=6.5 Hz, 1.5 Hz, 2H), 7.51-7.45 (m, 3H), 7.43 (t, J=7.5 Hz, 2H),7.38 (t, J=7.5 Hz, 2H), 7.31-7.27 (m, 1H), 6.80 (s, 1H), 3.61 (s, 3H)ppm. ¹³C NMR (CDCl₃, 125 MHz): δ 173.7, 149.6, 137.3, 131.1, 129.2,129.1, 128.9, 128.7, 128.1, 128.0, 124.4, 111.5, 31.9 ppm. IR (thinfilm) 1676, 1622, 1596, 1564, 1534, 1475, 1354, 1300, 1280, 1201, 1025,905, 725 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₁₇H₁₆N₃O 278.1293;Found 278.1305.

4-Fluoro-N-(1-methyl-4-phenyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5e)

Prepared according to general procedure E from 4e (97 mg, 0.59 mmol),iPr₂NEt (0.38 mL, 2.16 mmol), chlorotrimethylsilane (0.08 mL, 0.62mmol), and 3a (100 mg, 0.54 mmol) to yield a white solid (82 mg, 56%).R_(f)=0.21 (4:1 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.28 (t,J=7.0 Hz, 2H), 7.46 (d, J=8.4, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.30 (t,J=7.9 Hz, 1H), 7.07 (t, J=8.6 Hz, 2H), 6.77 (s, 1H), 3.62 (s, 3H) ppm.¹³C NMR (CDCl₃, 125 MHz): δ 173.4, 164.7 (d, J_(CF)=248.8 Hz), 150.6,134.1, 130.9 (d, J_(CF)=8.9 Hz), 129.1, 128.2, 128.2, 125.9, 124.0,114.8 (d, J_(CF)=21.4 Hz), 110.9, 31.7 ppm. IR (thin film): 2945, 1678,1622, 1596, 1563, 1476, 1404, 1355, 1273, 1221, 1145, 1084, 1054, 1013,955, 893 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₁₇H₁₅N₃OF 296.1199;Found 296.1217.

2-Fluoro-N-(4-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5f)

Prepared according to general procedure E from 4a (126 mg, 0.77 mmol),iPr₂NEt (0.37 mL, 2.1 mmol), chlorotrimethylsilane (0.10 mL, 0.81 mmol),and 3b (150 mg, 0.70 mmol) to yield a white solid (166.3 mg, 73%).R_(f)=0.16 (6:4 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.11 (dt, J=8Hz, 1 Hz, 1H), 7.47-7.38 (m, 3H), 7.19 (t, J=7.5 Hz, 1H), 7.12 (dd, J=8Hz, 3 Hz, 1H), 6.90 (d, J=8 Hz, 2H), 6.77 (s, 1H), 3.81 (s, 3H), 3.60(s, 3H). ¹³C NMR (126 MHz, Chloroform-d) δ 165.7, 156.78 (d, J=253.3Hz), 154.70, 142.6, 127.80 (d, J=9.0 Hz), 127.16 (d, J=1.9 Hz), 120.94,120.30, 119.25 (d, J=3.5 Hz), 117.59, 111.85 (d, J=23.7 Hz), 109.73,106.32, 50.67, 27.45. IR (thin film) 2950, 2836, 1684, 1614, 1560, 1511,1480, 1461, 1363, 1328, 1290, 1245, 1217, 1179, 1155, 1090, 1031, 957,909, 897, 832, 754, 729 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd forC₁₈H₁₇N₃O₂F 326.1305; Found 326.1309.

4-Methoxy-N-(4-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5 g)

Prepared according to general procedure E from 4b (135 mg, 0.77 mmol),iPr₂NEt (0.37 mL, 2.1 mmol), chlorotrimethylsilane (0.10 mL, 0.81 mmol),and 3b (150 mg, 0.70 mmol) to yield a white solid (171 mg, 73%).R_(f)=0.09 (6:4 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.24 (d J=8.5Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 6.93 (dd, J=9 Hz, 2 Hz, 4H), 6.70 (s,1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.64 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz):δ 173.6, 162.0, 159.5, 149.9, 130.5, 130.2, 128.6, 125.6, 121.3, 114.5,113.2, 109.9, 55.4, 55.3, 31.8 ppm. IR (thin film) 2937, 2837, 1670,1603, 1562, 1513, 1458, 1363, 1308, 1245, 1175, 1163, 1105, 1029, 957,908, 893, 883 cm⁻¹.

4-Chloro-N-(4-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5ga)

Prepared according to general procedure E from 4c (138 mg, 0.77 mmol),iPr₂NEt (0.37 mL, 2.1 mmol), chlorotrimethylsilane (0.10 mL, 0.81 mmol),and 5b (150 mg, 0.70 mmol) to yield a white solid (184.8 mg, 77%).R_(f)=0.24 (6:4 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 12.62 (br s,1H), 8.24 (dd, J=8.5 Hz, 1.5 Hz, 2H), 7.44-7.37 (m, 4H), 6.95 (dd, J=8.5Hz, 1.5 Hz, 2H), 6.69 (s, 1H), 3.85 (s, 3H), 3.67 (s, 3H). ¹³C NMR(CDCl₃, 125 MHz): δ 173.7, 159.7, 151.0, 136.8, 136.8, 130.2, 128.1,125.6, 125.3, 120.6, 114.6, 109.5, 55.4, 31.6 ppm. IR (thin film) 2937,2836, 1625, 1564, 1513, 1478, 1361, 1292, 1252, 1180, 1087, 1036, 1014,892, 830, 769 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₁₈H₁₇N₃O₂Cl342.1009; Found 342.1017.

N-(4-(4-Methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5h)

Prepared according to general procedure E from 4d (113 mg, 0.77 mmol),iPr₂NEt (0.37 mL, 2.1 mmol), chlorotrimethylsilane (0.10 mL, 0.81 mmol),and 3b (150 mg, 0.70 mmol) to yield a white solid (168 mg, 78%). ¹H NMR(CDCl₃, 500 MHz): δ 8.27 (d, J=6.5 Hz, 2H), 7.46-7.38 (m, 3H), 7.35 (d,J=9 Hz, 2H), 6.86 (d, J=9 Hz, 2H), 6.62 (s, 1H), 3.76 (s, 3H), 3.55 (s,3H). ¹³C NMR (CDCl₃, 125 MHz): δ 173.9, 159.5, 149.8, 137.7, 130.9,128.7, 128.0, 125.5, 121.3, 114.5, 110.1, 55.3, 31.7 ppm. IR (thin film)1623, 1566, 1539, 1513, 1478, 1365, 1299, 1251, 1180, 1036, 904, 831,722 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₁₈H₁₈N₃O₂ 308.1399;Found 308.1412.

4-Fluoro-N-(4-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5i)

Prepared according to general procedure E from 4e (84 mg, 0.51 mmol),iPr₂NEt (0.33 mL, 1.84 mmol), chlorotrimethylsilane (0.07 mL, 0.53mmol), and 3b (100 mg, 0.46 mmol) to yield a white solid (87 mg, 58%).R_(f)=0.52 (EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.26 (t, J=7.2 Hz, 2H),7.35 (d, J=7.7 Hz, 2H), 7.05 (t, J=8.3 Hz, 2H), 6.88 (d, J=7.8 Hz, 2H),6.61 (s, 1H), 3.78 (s, 3H), 3.7 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ173.2, 164.7 (d, J_(CF)=248.8 Hz), 159.6, 150.4, 134.2, 130.9 (d,J_(CF)=8.7 Hz), 125.8, 125.5, 120.8, 114.7 (d, J_(CF)=22.1 Hz), 114.5,109.7, 55.3, 31.7 ppm. IR (thin film): 1626, 1600, 1567, 1540, 1513,1478, 1365, 1253, 1189, 1147, 1078, 903 cm⁻¹.

2,4-Dichloro-N-(4-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5j)

Prepared according to general procedure E from 4f (165 mg, 0.77 mmol),iPr₂NEt (0.50 mL, 2.80 mmol), chlorotrimethylsilane (0.10 mL, 0.81mmol), and 3b (150 mg, 0.70 mmol) to yield a white solid (218 mg, 83%).R_(f)=0.41 (EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 7.82 (d, J=8.5, 1H),7.40-7.31 (m, 2H), 7.20 (d, J=8.2 Hz, 1H), 6.88 (d, J=9.1 Hz, 2H), 6.67(s, 1H), 3.78 (s, 3H), 3.55 (s, 3H), ppm. ¹³C NMR (CDCl₃, 125 MHz): δ173.1, 159.6, 136.6, 136.5, 135.3, 133.1, 131.8, 130.2, 126.6, 125.7,121.0, 120.9, 114.5, 110.2, 55.3, 31.9 ppm. IR (thin film): 2936, 2826,1688, 1625, 1555, 1511, 1464, 1357, 1326, 1291, 1246, 1197, 1178, 1139,1110, 1032, 957, 895 cm⁻¹.

N-(5-Benzyl-4-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-2-fluorobenzamide(5k)

Prepared according to general procedure E from 4a (67 mg, 0.41 mmol),iPr₂NEt (0.26 mL, 1.5 mmol), chlorotrimethylsilane (0.06 mL, 0.43 mmol),and 3c (150 mg, 0.37 mmol) to yield a white solid (136 mg, 89%).R_(f)=0.19 (6:4 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.11 (s, 1H),7.44-7.30 (m, 5H), 7.30-7.23 (m, 1H), 7.21-7.13 (m, 3H), 7.13-7.07 (m,1H), 6.96-6.89 (m, 2H), 4.12 (s, 2H), 3.81 (s, 3H), 3.38 (s, 3H). ¹³CNMR (125 MHz, CDCl₃) δ 171.8, 161.6 (d, J=254.1 Hz), 159.6, 148.7,137.0, 132.0 (d, J=8.8 Hz), 131.7 (d, J=1.9 Hz), 129.1, 128.1, 127.7,127.1, 126.3, 124.3, 123.7 (d, J=3.8 Hz), 121.9, 120.3, 116.6 (d, J=23.4Hz), 114.5, 55.3, 29.3, 29.2 ppm. IR (thin film) 2936, 2837, 1684, 1567,1513, 1494, 1480, 1452, 1355, 1290, 1248, 1177, 1031, 994, 906, 833, 758cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₂₅H₂₃N₃O₂F 416.1774; Found416.1776.

N-(5-Benzyl-4-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-4-methoxybenzamide(5l)

Prepared according to general procedure E from 4b (73 mg, 0.41 mmol),iPr₂NEt (0.26 mL, 1.5 mmol), chlorotrimethylsilane (0.06 mL, 0.43 mmol),and 3c (150 mg, 0.37 mmol) to yield a white solid (113 mg, 72%).R_(f)=0.16 (6:4 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.26 (d, J=9Hz, 2H), 7.40-7.36 (m, 2H), 7.36-7.32 (m, 2H), 7.29-7.24 (m, 1H), 7.17(d, J=7 Hz, 2H), 6.92 (dd, J=8.5 Hz, 2 Hz, 4H), 4.10 (s, 2H), 3.84 (s,3H), 3.81 (s, 3H), 3.40 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 174.2,161.8, 159.6, 150.4, 137.0, 130.9, 130.5, 129.1, 128.1, 127.7, 127.1,122.8, 121.7, 119.6, 114.6, 113.1, 55.4, 55.3, 29.3, 29.0 ppm. IR (thinfilm) 2935, 2837, 1670, 1568, 1514, 1454, 1351, 1291, 1246, 1165, 1113,1029, 992, 906, 893, 833, 778 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd forC₂₆H₂₆N₃O₃ 428.1974; Found 428.1981.

N-(5-Benzyl-4-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-4-chlorobenzamide(5m)

Prepared according to general procedure E from 4c (74 mg, 0.41 mmol),iPr₂NEt (0.26 mL, 1.5 mmol), chlorotrimethylsilane (0.06 mL, 0.43 mmol),and 3c (150 mg, 0.37 mmol) to yield a white solid (130 mg, 81%).R_(f)=0.34 (6:4 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.23 (d, J=8Hz, 2H), 7.40-7.35 (m, 4H), 7.35-7.32 (m, 2H), 7.30-7.26 (m, 1H), 7.17(d, J=7.5 Hz, 2H), 6.93 (d, J=9 Hz, 2H), 4.10 (s, 2H), 3.82 (s, 3H),3.40 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 173.6, 159.7, 150.6, 137.0,136.8, 136.7, 130.2, 129.1, 128.1, 128.0, 127.6, 127.2, 122.5, 121.2,119.8, 114.6, 55.4, 29.3, 29.0 ppm. IR (thin film) 2934, 2836, 1634,1566, 1512, 1476, 1349, 1291, 1249, 1178, 1086, 1031, 1012, 992, 907,891, 832, 768 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₂₅H₂₃N₃O₂C;432.1479; Found 432.1483.

N-(5-Benzyl-4-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5n)

Prepared according to general procedure E from 4d (60 mg, 0.41 mmol),iPr₂NEt (0.26 mL, 1.5 mmol), chlorotrimethylsilane (0.06 mL, 0.43 mmol),and 3c (150 mg, 0.37 mmol) to yield a white solid (125 mg, 85%).R_(f)=0.25 (6:4 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.32 (d,J=7.5 Hz, 2H), 7.46-7.40 (m, 3H), 7-40-7.37 (m, 2H), 7.37-7.32 (m, 2H),7.30-7.25 (m, 1H), 7.17 (d, J=7.5 Hz, 2H), 6.93 (d, J=8.5 Hz, 2H), 4.10(s, 2H), 3.81 (s, 3H), 3.41 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 174.6,159.6, 150.5, 138.3, 137.0, 130.7, 129.1, 128.7, 128.7, 128.1, 127.9,127.7, 127.1, 122.7, 121.5, 119.8, 114.6, 55.4, 29.3, 29.0 ppm. IR (thinfilm) 3061, 2934, 2836, 1676, 1635, 1568, 1541, 1513, 1453, 1350, 1291,1248, 1177, 1066, 1028, 993, 907, 891, 832 cm⁻¹. HRMS (ESI-TOF) m/z:[M+H]+ Calcd for C₂₅H₄₃N₃O₂ 398.1869; Found 398.1876.

2-Fluoro-N-(5-isopropyl-1-methyl-4-phenyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5o)

Prepared according to general procedure E from 4a (118 mg, 0.72 mmol),iPr₂NEt (0.34 mL, 1.98 mmol), chlorotrimethylsilane (0.1 mL, 0.76 mmol),and 3d (150 mg, 0.66 mmol) to yield a white solid (152 mg, 66%).R_(f)=0.29 (6:4 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.09 (dt,J=7.5 Hz, 1.5 Hz, 1H), 7.43-7.33 (m, 6H), 7.16 (t, J=8 Hz, 1H), 7.08(dd, J=8.5 Hz, 2.5 Hz, 1H), 3.67 (s, 3H), 3.29-3.22 (m, 1H), 1.31 (d,J=7.5 Hz, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 172.1, 161.5 (d, J_(CF)=254.1Hz), 149.0, 131.8, 131.7 (d, J_(CF)=2.4 Hz), 130.2, 128.7 (d, J_(CF)=7.2Hz), 128.3, 128.2, 126.7 (d, J_(CF)=9.7 Hz), 123.6 (d, J_(CF)=3.6 Hz),121.6, 116.5 (d, J_(CF)=23.3 Hz), 30.2, 24.5, 21.3 ppm. IR (thin film)2969, 1685, 1565, 1481, 1447, 1357, 1260, 1219, 1154, 1093, 1047, 1033,987, 907, 897, 757 cm⁻¹.

N-(5-Isopropyl-1-methyl-4-phenyl-1,3-dihydro-2H-imidazol-2-ylidene)-4-methoxybenzamide(5p)

Prepared according to general procedure E from 4b (127 mg, 0.72 mmol),iPr₂NEt (0.34 mL, 1.98 mmol), chlorotrimethylsilane (0.1 mL, 0.76 mmol),and 3d (150 mg, 0.66 mmol) to yield a white solid (158.8 mg, 66%).R_(f)=0.26 (6:4 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.24 (d,J=8.5 Hz, 2H), 7.43-7.36 (m, 4H), 7.36-7.32 (m, 1H), 6.90 (d, J=8.5 Hz,2H), 3.81 (s, 3H), 3.68 (s, 3H), 3.28-3.21 (m, 1H), 1.29 (d, J=7.5 Hz,6H). ¹³C NMR (CDCl₃, 125 MHz): δ 174.0, 161.8, 150.2, 131.0, 130.5,130.2, 128.7, 128.6, 128.3, 127.7, 120.8, 113.1, 55.3, 30.0, 24.5, 21.3ppm. IR (thin film) 2968, 1669, 1567, 1538, 1464, 1354, 1307, 1248,1178, 1162, 1030, 987, 906, 779, 766 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+Calcd for C₂₁H₂₄N₃O₂ 350.1869; Found 250.1870.

4-Chloro-N-(5-isopropyl-1-methyl-4-phenyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5q)

Prepared according to general procedure E from 4c (130 mg, 0.72 mmol),iPr₂NEt (0.34 mL, 1.98 mmol), chlorotrimethylsilane (0.1 mL, 0.76 mmol),and 4d (150 mg, 0.66 mmol) to yield a white solid (150 mg, 64%).R_(f)=0.42 (6:4 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.26-8.20 (m,2H), 7.45-7.41 (m, 2H), 7.40-7.33 (m, 5H), 3.72 (s, 3H), 3.30-3.22 (m,1H), 1.32 (d, J=7 Hz, 6H). ¹³C NMR (CDCl₃, 125 MHz): δ 173.6, 150.6,137.2, 136.5, 130.2, 129.6, 128.8, 128.6, 128.5, 128.0, 127.7, 120.1,30.0, 24.5, 21.3 ppm. IR (thin film) 2969, 1623, 1565, 1536, 1473, 1395,1339, 1163, 1087, 1046, 1013, 987, 906, 892, 851, 767 cm⁻¹. HRMS(ESI-TOF) m/z: [M+H]+ Calcd for C₂₀H₂₁N₃OC₁ 354.1373; Found 354.1377.

N-(5-Isopropyl-1-methyl-4-phenyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5r)

Prepared according to general procedure E from 4d (105 mg, 0.72 mmol),iPr₂NEt (0.34 mL, 1.98 mmol), chlorotrimethylsilane (0.1 mL, 0.76 mmol),and 3d (150 mg, 0.66 mmol) to yield a white solid (153 mg, 73%).R_(f)=0.39 (6:4 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.34-8.29 (m,2H), 7.47-7.35 (m, 8H), 3.71 (s, 3H), 3.29-3.22 (m, 1H), 1.31 (d, J=7Hz, 6H). ¹³C NMR (CDCl₃, 125 MHz): δ 174.5, 150.5, 138.5, 130.6, 129.9,128.8, 128.7, 128.6, 128.4, 127.9, 127.7, 120.4, 30.0, 24.5, 21.3 ppm.IR (thin film) 3061, 2968, 1676, 1622, 1592, 1567, 1540, 1466, 1353,1300, 1168, 1066, 1046, 1024, 987, 907, 892, 766 cm⁻¹. HRMS (ESI-TOF)m/z: [M+H]+ Calcd for C₂₀H₂₂N₃O 320.1763; Found 320.1769.

N-(1-Ethyl-4-(4-methoxyphenyl)-1,3-dihydro-2H-imidazol-2-ylidene)-2-fluorobenz-amide(5s)

Prepared according to general procedure E using 4a (34.40 mg, 0.15mmol), iPr₂NEt (0.09 mL, 0.53 mmol), chlorotrimethylsilane (0.02 mL,0.18 mmol), and 3e (29.50 mg, 0.18 mmol) to yield a white solid (40.20mg, 79%). R_(f)=0.4 (3:2 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.10(td, J=7.5, 2.0 Hz, 1H), 7.45 (d, J=8.5 Hz, 2H), 7.42-7.37 (m, 1H), 7.18(t, J=7.5 Hz, 1H), 7.10 (dd, J=8.5, 11.5 Hz, 1H), 6.91 (d, J=8.5 Hz.2H), 6.78 (s, 1H), 4.03 (q, J=7.5 Hz, 2H), 3.81 (s, 3H), 1.44 (t, J=7.5Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 162.6, 160.6, 159.4, 132.2 (d,J_(CF)=37.0 Hz), 131.8 (d, J_(CF)=8.0 Hz), 125.6, 123.7 (d, J_(CF)=15.0Hz), 122.0, 116.6, 116.2, 114.4, 108.8, 55.3, 40.1, 14.9.

4-Chloro-N-(1-ethyl-4-(4-methoxyphenyl)-1,3-dihydro-2H-imidazol-2-ylidene)benz-amide(5t)

Prepared according to general procedure E using 4c (0.10 g, 0.43 mmol),iPr₂NEt (0.27 mL, 1.56 mmol), chlorotrimethylsilane (0.07 mL, 0.54mmol), and 3e (94.27 mg, 0.52 mmol) to yield a white solid (76.0 mg,52%). R_(f)=0.3 (3:1 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 12.60(brs, 1H), 8.22 (d, J=9.0 Hz, 2H), 7.38 (dd, J=8.5, 12.5 Hz, 4H), 6.92(d, J=8.5 Hz, 2H), 6.69 (s, 1H), 4.07 (q, J=7.5 Hz, 2H), 3.81 (s, 3H),1.45 (t, J=7.5 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 173.6, 159.6, 150.4,136.9, 136.6, 130.2, 128.0, 125.5, 125.3, 120.7, 114.6, 107.8, 55.4,39.8, 14.8 ppm.

3-Chloro-N-(1-ethyl-4-(4-methoxyphenyl)-1,3-dihydro-2H-imidazol-2-ylidene)-benzamide(5u)

Prepared according to general procedure E using 4 g (0.15 g, 0.65 mmol),iPr₂NEt (0.41 mL, 2.35 mmol), chlorotrimethylsilane (0.10 mL, 0.81mmol), and 3e (0.14 g, 0.78 mmol) to yield a white solid (0.22 g,quant). R_(f)=0.3 (2:1 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 12.53(brs, 1H), 8.26 (s, 1H), 8.14 (d, J=7.5 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H),7.31 (dd, J=9.0, 15.0 Hz, 3H), 6.85 (d, J=8.5 Hz, 2H), 6.64 (s, 1H),4.00 (q, t=7.5 Hz, 2H), 3.74 (s, 3H), 1.38 (t, J=7.5 Hz, 3H). ¹³C NMR(CDCl₃, 125 MHz): δ 173.0, 159.5, 150.2, 140.4, 133.8, 130.5, 129.1,128.9, 126.9, 125.4, 125.2, 120.5, 114.5, 107.9, 55.3, 39.8, 14.8 ppm.

2-Chloro-N-(1-ethyl-4-(4-methoxyphenyl)-1,3-dihydro-2H-imidazol-2-ylidene)-benzamide(5v)

Prepared according to general procedure E using 4h (0.15 g, 0.65 mmol),iPr₂NEt (0.41 mL, 2.35 mmol), chlorotrimethylsilane (0.10 mL, 0.81mmol), and 3e (0.14 g, 0.78 mmol) to yield a white solid (0.22 g,quant). R_(f)=0.5 (2:1 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ (12.50(brs, 1H), 7.90-7.86 (m 1H), 7.44-7.38 (m, 3H), 7.31-7.26 (m, 2H), 6.93(d, J=9.0 Hz, 2H), 6.74 (s, 1H), 4.05 (q, J=7.5 Hz, 2H), 3.83 (s, 3H),1.44 (t, J=7.5 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 173.5, 159.4, 147.6,147.5, 147.5, 138.0, 131.9, 130.5, 130.4, 130.3, 130.2, 128.0, 126.4,125.6, 121.8, 114.4, 109.0, 55.3, 40.2, 14.9 ppm.

N-(1-Ethyl-4-(4-methoxyphenyl)-1,3-dihydro-2H-imidazol-2-ylidene)-4-fluoro-benzamide(5w)

Prepared according to general procedure E using 4e (0.10 g, 0.43 mmol),iPr₂NEt (0.27 mL, 1.56 mmol), chlorotrimethylsilane (0.07 mL, 0.54mmol), and 3e (85.7 mg, 0.52 mmol) to yield a white solid (0.14 g, 96%).R_(f)=0.7 (1:1 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 12.56 (brs,1H), 8.28 (t, J=9.0 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.05 (t, J=8.5 Hz,2H), 6.86 (d, J=8.5 Hz, 2H), 6.64 (s, 1H), 4.00 (q, J=7.0 Hz, 2H), 3.75(s, 3H), 1.38 (t, J=7.0 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 173.4,165.6, 163.6, 159.5, 150.2, 134.6, 135.6, 131.0 (d, J_(CF)=34.5 Hz),125.4 (d, J_(CF)=20.0 Hz), 120.8, 114.7, 114.5 (d, J_(CF)=8.5 Hz),107.8, 55.3, 39.8, 14.7.

N-(1-Ethyl-4-(4-methoxyphenyl)-1,3-dihydro-2H-imidazol-2-ylidene)-3-fluoro-benzamide(5x)

Prepared according to general procedure E using 4i (0.10 g, 0.43 mmol),iPr₂NEt (0.27 mL, 1.56 mmol), chlorotrimethylsilane (0.07 mL, 0.54mmol), and 3e (85.7 mg, 0.52 mmol) to yield a white solid (0.14 g, 98%).R_(f)=0.4 (5:2 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 12.61 (brs,1H), 8.06 (d, J=8.0 Hz, 1H), 7.99 (ddd, J=10.0, 2.5, 1.5 Hz, 1H), 7.41(d, J=9.0 Hz, 2H), 7.40-7.35 (m, 1H), 7.14 (td, J=8.5, 2.0 Hz, 1H), 6.94(d, J=8.0 Hz, 2H), 6.71 (s, 1H), 4.11 (q, J=7.5 Hz, 2H), 3.83 (s, 3H),1.47 (t, J=7.5 Hz, 3H).

4-Chloro-N-(1-ethyl-4-phenyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5y)

Prepared according to general procedure E using 4c (0.07 g, 0.35 mmol),iPr₂NEt (0.22 mL, 1.26 mmol), chlorotrimethylsilane (0.05 mL, 0.44mmol), and 3f (75.85 mg, 0.42 mmol) to yield a white solid (102.8 mg,90%). R_(f)=0.2 (5:1 hexanes/EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 12.72(brs, 1H), 8.23 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.45-7.35 (m,4H), 7.32 (t, J=7.5 Hz, 1H), 6.83 (s, 1H), 4.11 (q, J=7.5 Hz, 2H), 1.48(t, J=7.5 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 173.8, 150.8, 136.8,136.8, 130.2, 129.2, 128.2, 128.0, 125.0, 124.2, 109.0, 39.9, 14.8 ppm.

4-Chloro-N-(1-(4-methoxyphenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-3-ylidene)benzamide (5z)

Prepared according to general procedure E from 4c (122 mg, 0.68 mmol),iPr₂NEt (0.33 mL, 1.86 mmol), chlorotrimethylsilane (0.09 mL, 0.71mmol), and 3 g (150 mg, 0.62 mmol) to yield a white solid (134 mg, 59%).¹H NMR (CDCl₃, 500 MHz): δ 8.18 (d, J=9.0 Hz, 2H), 7.35 (d, J=9.0 Hz,2H), 7.33 (d, J=9.0 Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 4.03 (t, J=7.5 Hz,2H), 3.04 (t, J=7.5 Hz, 2H), 2.68-2.59 (m, 2H). ¹³C NMR (CDCl₃, 125MHz): δ 168.8, 154.0, 142.0, 132.1, 131.9, 125.3, 123.3, 120.6, 120.3,111.8, 116.9, 109.8, 50.6, 38.6, 23.3, 18.7 ppm. IR (thin film) 1572,1513, 1338, 1249, 1011, 891, 822, 764 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+Calcd for C₂₀H₁₉N₃O₂Cl 368.1166; Found 368.1174.

N-(4-(Benzo[d][1,3]dioxol-5-yl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-4-chlorobenzamide(5aa)

Prepared according to general procedure E from 4c (87 mg, 0.48 mmol),iPr₂NEt (0.32 mL, 1.76 mmol), chlorotrimethylsilane (0.07 mL, 0.51mmol), and 3h (100 mg, 0.44 mmol) to yield a white solid (108 mg, 69%).¹H NMR (CDCl₃, 500 MHz): δ 8.19 (d, J=9.0 Hz, 2H), 7.36 (d, J=8.5 Hz,2H), 6.96 (d, J=8.0 Hz, 2H), 6.92 (s, 1H), 6.83 (d, J=8.0 Hz, 2H), 6.67(s, 1H), 5.99 (s, 2H), 3.64 (s, 3H). LCMS [M+H]⁺ 356.1. IR (thin film)2969, 1738, 1558, 1528, 1345, 1232, 1036, 1012, 938, 900, 806, 756 cm⁻¹.HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₁₈H₁₅N₃O₃Cl 356.0802; Found356.0805.

N-(4-(Benzo[d][1,3]dioxol-5-yl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-2-fluorobenzamide(5ab)

Prepared according to general procedure E from 4a (79 mg, 0.48 mmol),iPr₂NEt (0.32 mL, 1.76 mmol), chlorotrimethylsilane (0.07 mL, 0.51mmol), and 3h (100 mg, 0.44 mmol) to yield a white solid (98 mg, 66%).¹H NMR (CDCl₃, 500 MHz): δ 8.10 (t, J=8.0 Hz, 1H), 7.44 (q, J=6.0 Hz,1H), 7.21 (t, J=7.5 Hz, 1H), 7.12-7.10 (m, 1H), 7.04-7.01 (m, 2H),6.81-6.79 (m, 2H), 5.96 (s, 2H), 3.61 (s, 3H). LCMS [M+H]+ 340.1. ¹³CNMR (125 MHz, CDCl₃) δ 164.1, 156.6 (d, J=252.6 Hz), 143.5, 142.5,128.1, 127.1 (d, J=1.9 Hz), 119.9, 119.3 (d, J=3.5 Hz), 113.3, 111.7 (d,J=23.7 Hz), 107.3, 103.9, 100.3, 96.5, 27.6 ppm. IR (thin film) 2970,1738, 1558, 1473, 1356, 1230, 1034, 932, 753 cm⁻¹. HRMS (ESI-TOF) m/z:[M+H]+ Calcd for C₁₈H₁₅N₃O₃F 340.1097; Found 340.1114.

4-Chloro-N-(1-methyl-4-(o-tolyl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5ac)

Prepared according to general procedure E from 4c (150 mg, 0.83 mmol),iPr₂NEt (0.53 mL, 3.0 mmol), chlorotrimethylsilane (0.11 mL, 0.86 mmol),and 3i (150 mg, 0.75 mmol) to yield a white solid (163 mg, 67%).R_(f)=0.46 (EtOAc); ¹H NMR (CDCl₃, 500 MHz): δ 8.27-8.15 (m, 2H),7.47-7.33 (m, 3H), 7.27-7.19 (m, 3H), 6.61 (s, 1H), 3.65 (s, 3H), 2.44(s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 173.7, 150.6, 136.8, 136.7, 135.2,131.3, 130.2, 130.2, 128.5, 128.0, 127.9, 127.4, 126.4, 124.4, 113.1,31.6, 21.3 ppm. IR (thin film): 2948, 1680, 1615, 1589, 1559, 1531,1481, 1396, 1355, 1291, 1192, 1161, 1085, 1055, 1013, 955, 907, 891cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₁₈H₁₇N₃OC₁ 326.1060; Found326.1076.

2-Fluoro-N-(1-methyl-4-(o-tolyl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5ad)

Prepared according to general procedure E from 4a (136 mg, 0.83 mmol),iPr₂NEt (0.53 mL, 3.0 mmol), chlorotrimethylsilane (0.11 mL, 0.86 mmol),and 3i (150 mg, 0.75 mmol) to yield a white solid (195 mg, 84%).R_(f)=0.32 (EtOAc). ¹H NMR (CDCl₃, 500 MHz): δ 8.09 (td, J=7.8, 1.8 Hz,1H), 7.48-7.42 (m, 1H), 7.42-7.30 (m, 1H), 7.25-7.18 (m, 3H), 7.20-7.12(m, 1H), 7.09 (ddd, J=11.4, 8.3, 1.2 Hz, 1H), 6.69 (s, 1H), 3.61 (s,3H), 2.43 (s, 3H). IR (thin film): 2951, 1684, 1592, 1540, 1481, 1449,1358, 1286, 1262, 1217, 1190, 1155, 1124, 1091, 955, 897 cm⁻¹.

4-Chloro-N-(1-methyl-4-(pyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5ae)

Prepared according to general procedure E from 4c (132 mg, 0.72 mmol),iPr₂NEt (0.60 mL, 3.6 mmol), chlorotrimethylsilane (0.1 mL, 0.77 mmol),and 3j (150 mg, 0.67 mmol) to yield a brown solid (143.2 mg, 57%). ¹HNMR (CDCl₃, 500 MHz): δ 8.57 (d, J=4.8 Hz, 1H), 8.24 (d, J=8.5 Hz, 2H),7.68 (td, J=7.7, 1.8 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.38 (d, J=8.6 Hz,2H), 7.17 (dd, J=7.5, 4.9 Hz, 1H), 7.07 (s, 1H), 3.67 (s, 3H). ¹³C NMR(CDCl₃, 125 MHz): δ 173.6, 150.9, 149.8, 146.8, 136.8, 136.7, 136.6,130.3, 128.1, 125.5, 122.4, 118.2, 113.0, 31.9 ppm. IR (thin film):1618, 1586, 1571, 1530, 1458, 1360, 1333, 1281, 1253, 1206, 1163, 1087,1015, 891 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₁₆H₁₄N₄OCl313.0856; Found 313.0868.

2-Fluoro-N-(1-methyl-4-(pyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5af)

Prepared according to general procedure E from 4a (120 mg, 0.72 mmol),iPr₂NEt (0.60 mL, 3.6 mmol), chlorotrimethylsilane (0.1 mL, 0.77 mmol),and 3j (150 mg, 0.67 mmol) to yield a brown solid (170 mg, 86%). ¹H NMR(CDCl₃, 500 MHz): δ 8.50 (d, J=5.0 Hz, 1H), 8.10 (t, J=8.0 Hz, 1H), 7.65(t, J=8.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.45 (q, J=6.0 Hz, 1H), 7.28(s, 1H), 7.21 (t, J=7.5 Hz, 1H), 7.15-7.09 (m, 1H), 3.64 (s, 3H). LCMS[M+H]+ 297.1. ¹³C NMR (125 MHz, CDCl₃) δ 168.0, 161.2 (d, J_(CF)=250.8Hz) 149.4 (d, J_(CF)=7.3 Hz), 136.6 (d, J_(CF)=2.8 Hz), 133.1, 132.0,131.9, 124.2, 123.5, 123.2 122.0, 121.9, 118.5, 116.6, 116.4, 116.0,32.7 ppm. IR (thin film) 1684, 1593, 1542, 1459, 1357, 1216, 895 cm⁻¹.HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₁₆H₁₄N₄OF 297.1152; Found297.1156.

4-Methoxy-N-(1-methyl-4-(pyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5ag)

Prepared according to general procedure E from 4b (129 mg, 0.73 mmol),iPr₂NEt (0.41 mL, 2.35 mmol), chlorotrimethylsilane (0.1 mL, 0.77 mmol),and 3j (150 mg, 0.67 mmol) to yield a brown solid (147 mg, 71%). ¹H NMR(CDCl₃, 500 MHz): δ 8.47 (d, J=8.5 Hz, 1H), 8.16 (d, J=7.5 Hz, 2H), 7.59(d, J=7.5 Hz, 1H), 7.43 (d, J=7.5 Hz, 1H), 7.10-7.06 (m, 2H), 6.89 (d,J=8.5 Hz, 1H), 3.83 (s, 3H), 3.60 (s, 3H) ppm. LCMS [M+H]⁺ 309.2.

3-Chloro-N-(1-methyl-4-(pyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5ah)

Prepared according to general procedure E from 4 g (131 mg, 0.73 mmol),iPr₂NEt (0.41 mL, 2.35 mmol), chlorotrimethylsilane (0.1 mL, 0.77 mmol),and 3j (150 mg, 0.67 mmol) to yield a brown solid (204 mg, 95%). ¹H NMR(CDCl₃, 500 MHz): δ 8.53 (d, J=5.0 Hz, 1H), 8.26 (s, 1H), 8.14 (d, J=8.0Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.33 (t, J=7.5Hz, 1H), 7.14 (t, J=6.0 Hz, 1H), 7.04 (s, 1H), 3.66 (s, 3H). LCMS [M+H]⁺313.1.

4-Chloro-N-(1-methyl-4-(pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5ai)

Prepared according to general procedure E from 4c (133 mg, 0.73 mmol),iPr₂NEt (0.60 mL, 3.35 mmol), chlorotrimethylsilane (0.1 mL, 0.77 mmol),and 3k (150 mg, 0.67 mmol) to yield a brown solid (154 mg, 73%). ¹H NMR(CDCl₃, 500 MHz): δ 8.82 (d, J=2.3 Hz, 1H), 8.58-8.52 (m, 1H), 8.18 (d,J=8.2 Hz, 2H), 7.79 (d, J=8.0, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.40-7.27(m, 2H), 6.94 (s, 1H), 3.69 (s, 3H) ppm. LCMS [M+H]⁺313.2.

4-Chloro-N-(4-(6-methoxypyridin-2-yl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5aj)

Prepared according to general procedure E from 4d (59 mg, 0.33 mmol),iPr₂NEt (0.18 mL, 1.04 mmol), chlorotrimethylsilane (0.04 mL, 0.34mmol), and 31 (75 mg, 0.30 mmol) to yield a brown solid (55 mg, 54%). ¹HNMR (CDCl₃, 500 MHz): δ 8.24 (d, J=9.0 Hz, 2H), 7.58 (t, J=7.5 Hz, 1H),7.37 (d, J=9.0 Hz, 2H), 7.05-7.03 (m, 2H), 6.65 (d, J=8.0 Hz, 1H), 4.05(s, 3H), 3.69 (s, 3H). LCMS [M+H]⁺ 343.1.

3-Fluoro-N-(1-methyl-4-(pyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5agx)

Prepared according to general procedure E from 4i (120 mg, 0.72 mmol),iPr₂NEt (0.60 mL, 3.6 mmol), chlorotrimethylsilane (0.1 mL, 0.77 mmol),and 3j (150 mg, 0.67 mmol) to yield a brown solid (122 mg, 62%). ¹H NMR(500 MHz, CDCl₃) δ 8.56 (dd, J=4.8, 1.4 Hz, 1H), 8.34-8.28 (m, 2H), 7.67(td, J=7.8, 1.6 Hz, 1H), 7.43 (dd, J=8.0, 1.2 Hz, 1H), 7.16 (ddd, J=7.7,4.9, 1.2 Hz, 1H), 7.12-7.05 (m, 3H), 3.66 (d, J=1.0 Hz, 3H). ¹³C NMR(125 MHz, CDCl₃) δ 173.4, 164.7 (d, J=249.9 Hz), 150.8, 149.7, 147.0,136.6, 134.3, 131.0 (d, J=8.9 Hz), 125.6, 122.3, 118.2, 114.8, 113.1,31.9. IR (thin film) 1559, 1537, 1455, 1361, 1255, 1214, 1200, 1148,1025, 929, 864 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₁₆H₁₄N₄OF297.1152; Found 297.1153.

4-Fluoro-N-(1-methyl-4-(pyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5ahx)

Prepared according to general procedure E from 4e (120 mg, 0.72 mmol),iPr₂NEt (0.60 mL, 3.6 mmol), chlorotrimethylsilane (0.1 mL, 0.77 mmol),and 3j (150 mg, 0.67 mmol) to yield a brown solid (134 mg, 68%). ¹H NMR(500 MHz, CDCl₃) δ 8.58-8.52 (m, 1H), 8.08 (d, J=7.7 Hz, 1H), 8.02-7.95(m, 1H), 7.65 (td, J=7.8, 1.8 Hz, 1H), 7.43-7.34 (m, 2H), 7.15 (dt,J=9.0, 4.7 Hz, 2H), 7.04 (s, 1H), 3.65 (s, 3H). ¹³C NMR (125 MHz, CDCl₃)δ 173.2, 162.7 (d, J=244.4 Hz), 149.7, 146.7, 140.8, 136.6, 129.3 (d,J=7.7 Hz), 124.4 (d, J=2.7 Hz), 122.4, 118.2, 117.5 (d, J=21.4 Hz),115.6 (d, J=22.3 Hz), 113.0, 31.9. IR (thin film): 1618, 1593, 1580,1534, 1504, 1360, 1229, 1208, 1146 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+Calcd for C₁₆H₁₄N₄OF 297.1152; Found 297.1160.

4-Bromo-N-(1-methyl-4-(pyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5aix)

Prepared according to general procedure E from 4j (164 mg, 0.72 mmol),iPr₂NEt (0.60 mL, 3.6 mmol), chlorotrimethylsilane (0.1 mL, 0.77 mmol),and 3j (150 mg, 0.67 mmol) to yield a white solid (154 mg, 64%).R_(f)=0.33 (EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.57 (d, J=4.8 Hz, 1H),8.21-8.15 (m, 2H), 7.72-7.65 (m, 1H), 7.58-7.52 (m, 2H), 7.43 (d, J=7.9Hz, 1H), 7.21-7.16 (m, 1H), 7.06 (s, 1H), 3.67 (s, 3H). ¹³C NMR (125MHz, CDCl₃) δ 173.6, 150.9, 149.8, 146.8, 137.2, 136.6, 131.0, 130.5,125.5, 122.4, 118.2, 113.0, 110.8, 31.9. IR (thin film): 1617, 1597,1567, 1527, 1458, 1362, 1332, 1205 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+Calcd for C₁₆H₁₄N₄OBr 357.0351; Found 357.0367.

Benzyl(1-methyl-4-(pyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)carbamate(5ajx)

Prepared according to general procedure E from potassiumbenzyloxycarbonylcyanamide (528 mg, 2.46 mmol), iPr₂NEt (1.20 mL, 6.72mmol), chlorotrimethylsilane (330 μL, 2.58 mmol), and 3j (500 mg, 2.24mmol) to yield a white solid (265 mg, 38%). ¹H NMR (500 MHz, CDCl₃) δ8.50 (dd, J=4.7, 1.7 Hz, 1H), 7.60-7.52 (m, 2H), 7.42 (d, J=7.9 Hz, 2H),7.35-7.27 (m, 3H), 7.14-7.06 (m, 2H), 5.21 (s, 2H), 3.51 (s, 3H). ¹³CNMR (126 MHz, CDCl₃) δ 149.4, 136.9, 136.5, 128.4, 128.1, 127.9, 122.0,118.4, 114.9, 67.1, 32.4. IR (thin film) 1726, 1622, 1573, 1456, 1380,1295, 1221, 1085, 1062, 1028, 992, 909 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+Calcd for C₁₇H₁₇N₄O₂ 309.1352; Found 309.1369.

4-Methoxy-N-(1-methyl-4-(pyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5akx)

Prepared according to general procedure E from 4b (129 mg, 0.73 mmol),iPr₂NEt (0.41 mL, 2.35 mmol), chlorotrimethylsilane (0.1 mL, 0.77 mmol),and 3j (150 mg, 0.67 mmol) to yield a brown solid (147 mg, 71%). ¹H NMR(CDCl₃, 500 MHz): δ 8.47 (d, J=8.5 Hz, 1H), 8.16 (d, J=7.5 Hz, 2H), 7.59(d, J=7.5 Hz, 1H), 7.43 (d, J=7.5 Hz, 1H), 7.10-7.06 (m, 2H), 6.89 (d,J=8.5 Hz, 1H), 3.83 (s, 3H), 3.60 (s, 3H) ppm. ¹³C NMR (125 MHz, CDCl₃)δ 171.9, 162.2, 149.5, 148.6, 136.5, 130.8, 130.4, 130.2, 121.9, 118.3,114.7, 113.3, 112.9, 112.9, 55.3, 32.3 ppm. IR (thin film) 1557, 1524,1458, 1336, 1325, 1246, 1251, 1158, 1025, 891 cm⁻¹. HRMS (ESI-TOF) m/z:[M+H]+ Calcd for C₁₇H₁₇N₄O₂ 309.1352; Found 309.1357.

3-Chloro-N-(1-methyl-4-(pyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5al)

Prepared according to general procedure E from 4 g (131 mg, 0.73 mmol),iPr₂NEt (0.41 mL, 2.35 mmol), chlorotrimethylsilane (0.1 mL, 0.77 mmol),and 3j (150 mg, 0.67 mmol) to yield a brown solid (204 mg, 95%).R_(f)=0.24 (EtOAc). ¹H NMR (CDCl₃, 500 MHz): δ 8.53 (d, J=5.0 Hz, 1H),8.26 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.40 (d,J=8.5 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.14 (t, J=6.0 Hz, 1H), 7.04 (s,1H), 3.66 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 172.9, 149.8, 146.9,140.0, 136.6, 133.9, 130.7, 129.2, 129.0, 126.9, 122.4, 118.2, 113.1,32.0 ppm. IR (thin film) 1560, 1539, 1456, 1364, 1326, 1243, 1205, 1149,1053, 1024, 902 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₁₆H₁₄N₄OC₁313.0856; Found 313.0864.

2-Chloro-N-(1-methyl-4-(pyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5am)

Prepared according to general procedure E from 4h (131 mg, 0.73 mmol),iPr₂NEt (0.41 mL, 2.35 mmol), chlorotrimethylsilane (0.1 mL, 0.77 mmol),and 3j (150 mg, 0.67 mmol) to yield a brown solid (172 mg, 85%).R_(f)=0.23 (EtOAc). R_(f)=0.23 (EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.58(s, 1H), 8.31 (s, 1H), 8.18 (d, J=7.5 Hz, 1H), 7.70 (t, J=7.5 Hz, 1H),7.49-7.41 (m, 2kH), 7.41-7.34 (m, 1H), 7.19 (d, J=6.4 Hz, 1H), 7.09 (s,1H), 3.70 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 173.3, 151.0, 149.8,148.2, 146.7, 140.2, 136.6, 133.9, 130.6, 129.2, 129.0, 126.9, 122.4,118.2, 112.9, 32.0. IR (thin film) 1560, 1523, 1501, 1452, 1369, 1330,1240, 1207, 1149, 1066, 984, 901 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcdfor C₁₆H₁₄N₄OC₁ 313.0856; Found 313.0859.

2,4-Dichloro-N-(1-methyl-4-(pyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5an)

Prepared according to general procedure E from 4f (157 mg, 0.73 mmol),iPr₂NEt (0.41 mL, 2.35 mmol), chlorotrimethylsilane (0.1 mL, 0.77 mmol),and 3j (150 mg, 0.67 mmol) to yield a brown solid (183 mg, 79%). ¹H NMR(500 MHz, CDCl₃) δ 8.52 (d, J=4.9 Hz, 1H), 7.88-7.82 (m, 1H), 7.64 (t,J=7.7 Hz, 1H), 7.46-7.37 (m, 2H), 7.22 (dd, J=8.4, 2.1 Hz, 1H),7.17-7.08 (m, 2H), 3.60 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 168.9,145.7, 145.0, 143.3, 132.6, 132.5, 131.5, 129.2, 127.9, 126.2, 122.7,118.4, 114.4, 109.8, 28.3. IR (thin film): 1690, 1618, 1548, 1458, 1352,1209, 1140, 1100, 1046, 992, 894 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcdfor C₁₆H₁₃N₄OCl₂ 347.0466; Found 347.0471.

4-Chloro-N-(1-methyl-4-(pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5ao)

Prepared according to general procedure E from 4c (133 mg, 0.73 mmol),iPr₂NEt (0.60 mL, 3.35 mmol), chlorotrimethylsilane (0.1 mL, 0.77 mmol),and 3k (150 mg, 0.67 mmol) to yield a brown solid (154 mg, 73%). ¹H NMR(CDCl₃, 500 MHz): δ 8.82 (d, J=2.3 Hz, 1H), 8.58-8.52 (m, 1H), 8.18 (d,J=8.2 Hz, 2H), 7.79 (d, J=8.0, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.40-7.27(m, 2H), 6.94 (s, 1H), 3.69 (s, 3H) ppm. IR (thin film) 1675, 1566,1456, 1272, 1194, 1088, 947, 849, 819 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+Calcd for C₁₆H₁₄N₄OC₁ 313.0856; Found 313.0862.

4-Chloro-N-(4-(6-methoxypyridin-2-yl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5ap)

Prepared according to general procedure E from 4d (59 mg, 0.33 mmol),iPr₂NEt (0.18 mL, 1.04 mmol), chlorotrimethylsilane (0.04 mL, 0.34mmol), and 31 (75 mg, 0.30 mmol) to yield a brown solid (55 mg, 54%).R_(f)=−0.46 (6:4 hexanes/EtOAc). ¹H NMR (CDCl₃, 500 MHz): δ 8.24 (d,J=9.0 Hz, 2H), 7.58 (t, J=7.5 Hz, 1H), 7.37 (d, J=9.0 Hz, 2H), 7.05-7.03(m, 2H), 6.65 (d, J=8.0 Hz, 1H), 4.05 (s, 3H), 3.69 (s, 3H). ¹³C NMR(125 MHz, CDCl₃) δ 173.8, 163.9, 150.7, 144.2, 139.1, 136.8, 130.3,128.1, 125.2, 112.7, 110.9, 110.0, 53.6, 31.9 ppm. IR (thin film) 1589,1558, 1467, 1353, 1325, 1290, 1086, 1013 cm⁻¹. HRMS (ESI-TOF) m/z:[M+H]+ Calcd for C₁₇H₁₆N₄O₂Cl 343.0962; Found 343.0971.

4-Chloro-N-(4-(4-methoxypyridin-2-yl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5aq)

Prepared according to general procedure E from 4c (118 mg, 0.65 mmol),iPr₂NEt (362 μL, 2.10 mmol), chlorotrimethylsilane (86 μL, 0.68 mmol),and 3m (150 mg, 0.59 mmol) to yield a brown solid (152 mg, 75%).R_(f)=0.38 (EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 10.16 (s, 1H), 8.37 (d,J=5.7 Hz, 1H), 7.84-7.74 (m, 2H), 7.64 (s, 1H), 7.30-7.20 (m, 3H), 6.65(dd, J=5.7, 2.5 Hz, 1H), 4.12 (s, 3H), 3.79 (s, 3H). ¹³C NMR (125 MHz,CDCl₃) δ 163.2, 161.2, 148.7, 147.0, 138.3, 135.3, 134.5, 129.7, 126.3,126.0, 110.4, 107.3, 104.8, 52.5, 33.6. IR (thin film): 1663, 1594,1562, 1487, 1454, 1410, 1307, 1272, 1033 cm⁻¹.

4-Chloro-N-(4-(3-methoxypyridin-2-yl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5ar)

Prepared according to general procedure E from 4c (118 mg, 0.65 mmol),iPr₂NEt (362 μL, 2.10 mmol), chlorotrimethylsilane (86 μL, 0.68 mmol),and 3n (150 mg, 0.59 mmol) to yield a brown solid (115 mg, 57%).R_(f)=0.29 (EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.26 (dd, J=8.5, 1.0 Hz,2H), 8.20 (d, J=4.5 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.23-7.19 (m, 2H),7.18-7.13 (m, 1H), 3.97 (s, 3H), 3.65 (s, 3H). ¹³C NMR (125 MHz, CDCl₃)δ 171.0, 149.6, 147.6, 138.6, 134.6, 134.0, 133.6, 127.7, 127.6, 125.4,119.9, 119.7, 114.9, 113.4, 52.9, 29.2. IR (thin film): 1612, 1590,1565, 1534, 1468, 1369, 1354, 1278, 1222, 1013 cm⁻¹.

4-Chloro-N-(1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5as)

Prepared according to general procedure E from 4c (68 mg, 0.38 mmol),iPr₂NEt (211 μL, 1.20 mmol), chlorotrimethylsilane (50 μL, 0.39 mmol),and 3o (100 mg, 0.34 mmol) to yield a white solid (87 mg, 67%).R_(f)=0.62 (EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J=8.0 Hz, 2H),7.85 (t, J=8.0 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.53 (d, J=7.7 Hz, 1H),7.39 (d, J=8.1 Hz, 2H), 7.23 (s, 1H), 3.68 (s, 2H). ¹³C NMR (125 MHz,CDCl₃) δ 172.9, 148.3 (q, J=35.0 Hz), 148.0, 138.1, 137.3, 135.7, 130.2,128.2, 121.2 (q, J=274.3 Hz) 120.7, 118.6, 118.5, 115.4, 32.2. IR (thinfilm) 1561, 1532, 1368, 1332, 1159, 1130, 1110, 1087, 1041, 1013, 806,767 cm⁻¹. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C₁₇H₁₃N₄OF₃Cl 381.0730;Found 381.0741.

3-Chloro-N-(1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5at)

Prepared according to general procedure E from 4 g (68 mg, 0.37 mmol),iPr₂NEt (0.18 mL, 1.03 mmol), chlorotrimethylsilane (0.05 mL, 0.40mmol), and 3o (100 mg, 0.34 mmol) to yield a white solid (77 mg, 59%).R_(f)=−0.23 (6:4 hexanes/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.22 (t,J=2.1 Hz, 1H), 8.12 (d, J=7.7 Hz, 1H), 7.80 (t, J=7.7 Hz, 1H), 7.54 (d,J=8.1 Hz, 1H), 7.50 (dd, J=7.7, 2.1 Hz, 1H), 7.41 (d, J=7.3 Hz, 1H),7.38-7.31 (m, 1H), 7.14 (s, 1H), 3.64 (s, 2H). ¹³C NMR (126 MHz, CDCl₃)δ 172.7, 148.2 (q, J=35.1 Hz), 147.8, 139.4, 138.0, 134.0, 130.9, 129.3,129.0, 126.8, 121.2 (q, J=274.3 Hz), 120.8, 118.6 (d, J=2.9 Hz), 115.2,32.1. IR (thin film) 1541, 1359, 1333, 1128, 1110, 778 cm⁻¹. HRMS(ESI-TOF) m/z: [M+H]+ Calcd for C₁₇H₁₃N₄OF₃Cl 381.0730; Found 381.0739.

2-Chloro-N-(1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5au)

Prepared according to general procedure E from 4c (68 mg, 0.37 mmol),iPr₂NEt (0.18 mL, 1.03 mmol), chlorotrimethylsilane (0.05 mL, 0.40mmol), and 3o (100 mg, 0.34 mmol) to yield a white solid (19 mg, 14%).R_(f)=0.60 (EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 7.83-7.80 (m, 2H),7.69-7.68 (m, 1H), 7.52-7.41 (m, 3H), 7.38-7.29 (m, 2H), 3.71 (s, 3H).¹³C NMR (126 MHz, CDCl₃) δ 165.1, 145.9, 143.3 (q, J=34.6 Hz), 133.2,131.0, 126.7, 126.5, 125.6, 125.5, 122.1, 116.6 (q, J=274.3 Hz), 116.1,113.4, 28.5. IR (thin film) 1692, 1602, 1561, 1471, 1341, 1306, 1257,1185, 1137, 1115 cm⁻¹.

4-Chloro-N-(4-(6-fluoropyridin-2-yl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5av)

Prepared according to general procedure E from 4c (370 mg, 2.05 mmol),iPr₂NEt (1.07 mL, 5.98 mmol), chlorotrimethylsilane (270 μL, 2.14 mmol),and 3p (350 mg, 1.71 mmol) to yield a white solid (372 mg, 66%).R_(f)=0.60 (EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.23 (d, J=8.1 Hz, 2H),7.81 (q, J=7.8 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.38-7.33 (m, 1H), 7.19(s, 1H), 6.82 (dd, J=8.1, 2.7 Hz, 1H), 3.70 (s, 3H). ¹³C NMR (125 MHz,CDCl₃) δ 166.2, 163.1 (d, J=235.0 Hz), 152.2 (d, J=14.1 Hz), 143.1,140.1, 137.8, 136.7, 131.8, 130.3, 129.2, 121.0, 115.9, 106.9 (d, J=37.3Hz), 33.2.

4-Chloro-N-(1-ethyl-4-(pyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5aw)

Prepared according to general procedure E from 4c (126 mg, 0.70 mmol),iPr₂NEt (392 μL, 2.20 mmol), chlorotrimethylsilane (92 μL, 0.72 mmol),and 3q (150 mg, 0.63 mmol) to yield a white solid (159 mg, 77%). ¹H NMR(500 MHz, CDCl₃) δ 8.61-8.57 (m, 1H), 8.25 (d, J=8.5 Hz, 2H), 7.70 (td,J=7.7, 1.8 Hz, 1H), 7.49-7.45 (m, 1H), 7.42-7.37 (m, 2H), 7.19 (ddd,J=7.5, 4.8, 1.0 Hz, 1H), 7.13 (s, 1H), 4.14 (q, J=7.3 Hz, 2H), 1.50 (t,J=7.3 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 171.1, 147.3, 144.3, 134.3,134.2, 134.1, 127.7, 126.3, 125.5, 122.8, 119.8, 115.6, 108.7, 37.5,12.2. IR (thin film): 1615, 1591, 1567, 1560, 1459, 1397, 1378, 1338,1088 cm⁻¹.

4-Chloro-N-(1-methyl-4-(6-methylpyridin-2-yl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide(5ax)

Prepared according to general procedure E from 4c (108 mg, 0.60 mmol),iPr₂NEt (311 μL, 1.75 mmol), chlorotrimethylsilane (79 μL, 0.63 mmol),and 3r (100 mg, 0.50 mmol) to yield a white solid (47 mg, 27%). ¹H NMR(500 MHz, CDCl₃) δ 8.24 (d, J=8.1 Hz, 2H), 7.52 (t, J=7.5 Hz, 1H), 7.38(d, J=8.1 Hz, 2H), 7.17 (d, J=7.5 Hz, 1H), 7.00 (d, J=7.5 Hz, 1H), 6.94(s, 1H), 3.61 (s, 3H), 2.54 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 168.6,154.0, 141.3, 132.0, 132.0, 125.5, 125.4, 123.3, 123.2, 120.6, 117.2,110.6, 107.9, 27.1, 19.7.

N-(4-(6-(tert-Butyl)pyridin-2-yl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-4-chlorobenzamide(5ay)

Prepared according to general procedure E from 4c (90 mg, 0.50 mmol),iPr₂NEt (255 μL, 1.42 mmol), chlorotrimethylsilane (65 μL, 0.51 mmol),and 3s (100 mg, 0.41 mmol) to yield a white solid (43 mg, 27%). ¹H NMR(500 MHz, CDCl₃) δ 8.26 (d, J=8.2 Hz, 2H), 7.62 (t, J=7.8 Hz, 1H), 7.38(d, J=8.3 Hz, 2H), 7.24 (d, J=7.8 Hz, 2H), 7.02 (s, 1H), 3.67 (s, 3H),1.42 (s, 9H). ¹³C NMR (125 MHz, CDCl₃) δ 168.9, 164.8, 146.0, 140.4,132.1, 132.0, 126.0, 125.6, 123.3, 121.0, 113.2, 110.4, 107.7, 32.9,27.2, 25.4.

All publications, including patents and patent applications, in thisapplication are incorporated herein by reference in their entirety,except insofar as they expressly contradict the present application(e.g., two contradictory definitions of the same term). This includesU.S. application Ser. No. 15/268,410 (filed Sep. 16, 2016),International Application No. PCT/US2015/021602 (filed Mar. 19, 2015),and U.S. Provisional Application Nos. 61/955,761 (filed Mar. 19, 2014)and 62/051,863 (filed Sep. 17, 2014).

What is claimed is:
 1. A composition for therapeutic use, thecomposition comprising a 2-(acylamino)imidazole compound of structure I:

or a salt thereof; wherein: R¹ is a member selected from the groupconsisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl; wherein if R¹ is aryl, arylalkyl, heteroaryl, orheteroarylalkyl, then R¹ is unsubstituted or optionally substituted withfrom one to five substituents independently selected from the groupconsisting of alkyl, cyano, acyl, halo, hydroxy, alkoxy, amino,alkylamino, acylamino, thio, and alkylthio; X is a member selected fromthe group consisting of a bond, O, and NR^(5a); Y is a member selectedfrom the group consisting of O, S, or NR^(5b); or, when X is O or abond, Y is O; R² is a member independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, and arylalkyl; or, alternatively,R² and R⁷ join to form an additional heterocyclyl fused ring; R⁴ is amember independently selected from the group consisting of aryl andheteroaryl, wherein R⁴ is unsubstituted or has from one to five R^(6a)substituents; R^(5a) and R^(5b) are each a member independently selectedfrom the group consisting of hydrogen, alkyl, fluoroalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, and heteroarylalkyl;each of the R^(6a) members is independently selected from the groupconsisting of alkyl, hydroxy, alkoxy, aminoalkoxy, alkylamino,alkylaminoalkoxy, alkenyl, alkynyl, aryl, aryloxy, arylamino,cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkoxy,cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocycyloxy,heterocycylalkyloxy, heterocycylamino, heterocycylalkylamino, halo,haloalkyl, fluoroalkyloxy, arylalkyl, arylalkyloxy, arylalkylamino,heteroaryl, heteroaryloxy, heteroarylamino, heteroarylalkyl,heteroarylalkyloxy, and heteroarylalkylamino; or, alternatively, a pairof adjacent R^(6n) members join to form an additional fused ring that isselected from the group consisting of cycloalkyl, aryl, heterocyclyl,and heterocycloaryl; and R⁷ is a member independently selected from thegroup consisting of hydrogen, halo, methyl, trifluoromethyl, ethyl, andisopropyl; or, alternatively, R² and R⁷ join to form an additionalheterocyclyl fused ring; wherein the composition has <2% (w/w) ofN²,N²-diacylation; and wherein the composition has <2% (w/w) of acylregioisomers.
 2. The composition of claim 1, wherein R⁴ is heteroaryl,and wherein the R⁴ heteroaryl ring incorporates at least one hydrogenbond acceptor selected from the group consisting of N, O, and S.
 3. Thecomposition of claim 2, wherein R⁴ is selected from the group consistingof

wherein A¹ is a hydrogen bond acceptor selected from the groupconsisting of N, O, and S; A², A³, A⁴, and A⁵ are each independentlyselected from the group consisting of N, O, S, and CR^(6a); with theproviso that R⁴ does not have a formal charge.
 4. The composition ofclaim 1, wherein the 2-aminoimidazole compound is substantially freefrom an impurity selected from the group consisting of

or a salt thereof.
 5. The composition of claim 1, wherein R¹ is a memberselected from the group consisting of alkyl, aryl, arylalkyl, andheteroaryl.
 6. The composition of claim 5, wherein R¹ is a memberselected from the group consisting of isopropyl, sec-butyl, phenyl,2-bromophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,2-fluorophenyl, 4-fluorophenyl, 4-methoxyphenyl,3,4-methylenedioxyphenyl, 3-trifluoromethylphenyl, and 2-thiazolyl. 7.The composition of claim 5, wherein R¹ is 4-chlorophenyl.
 8. Thecomposition of claim 1, wherein X is a bond.
 9. The composition of claim1, wherein X is NR^(5a); and wherein Y is NR^(5b).
 10. The compositionof claim 1, wherein Y is O.
 11. The composition of claim 10, wherein Xis O.
 12. The composition of claim 1, wherein R² is a member selectedfrom the group consisting of alkyl, alkenyl, and arylalkyl.
 13. Thecomposition of claim 12, wherein R² is alkyl.
 14. The composition ofclaim 13, wherein R² is methyl or ethyl.
 15. The composition of claim13, wherein R² is methyl.
 16. The composition of claim 1, wherein A¹,A², A³, A⁴, and A⁵ are each an independently selected CH or CR^(6a). 17.The composition of claim 1, wherein only one of A¹, A², A³, A⁴, and A⁵is N.
 18. The composition of claim 1, wherein R⁴ is selected from thegroup consisting of pyridyl, pyrazinyl, imidazolyl, pyrazinyl, andoxazoyl; and wherein R⁴ is unsubstituted or has from one to four R^(6n)substituents.
 19. The composition of claim 1, wherein R^(5a) and R^(5b)are each a member independently selected from the group consisting ofhydrogen, alkyl, fluoroalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, arylalkyl, and heteroarylalkyl.
 20. The composition ofclaim 1, wherein each of the R^(6n) members is independently selectedfrom the group consisting of alkyl, hydroxy, alkoxy, aryl, aryloxy,cycloalkyl, cycloalkoxy, cycloalkylalkoxy, heterocyclyl, heterocycyloxy,heterocycylalkyloxy, halo, fluoroalkyl, fluoroalkyloxy, heteroaryl,heteroaryloxy, arylalkyl, arylalkyloxy, arylalkylamino, andheteroarylalkyloxy.
 21. The composition of claim 1, wherein each of theR^(6a) members is independently selected from the group consisting ofalkyl, hydroxy, alkoxy, cycloalkylalkoxy, halo, fluoroalkyl,fluoroalkyloxy, and arylalkyloxy.
 22. The composition of claim 1,wherein each of the R^(6n) members is independently selected from thegroup consisting of alkyl, hydroxy, and alkoxy.
 23. The composition ofclaim 1, wherein R⁴ is unsubstituted.
 24. The composition of claim 1,wherein

has from one to three hydroxyl or alkoxy substituents.
 25. Thecomposition of claim 1, wherein A³ is C(OH) or C(OMe).
 26. Thecomposition of claim 1, wherein R⁷ is methyl, isopropyl, or hydrogen.27. The composition of claim 1, wherein R⁷ is hydrogen.
 28. Thecomposition of claim 1, the composition comprising a compound that isselected from the group consisting of

and a salt thereof.
 29. The composition of claim 1, wherein thecomposition comprises the compound

or a salt thereof.
 30. A method of treating cancer, the methodcomprising administering the composition of claim 1 to a patient withcancer, thereby treating the patient.
 31. The method of claim 30,wherein the cancer is breast cancer.
 32. The method of claim 30, whereinthe composition comprises the compound

or a salt thereof.